Tetracyclic bromodomain inhibitors

ABSTRACT

wherein R1, R2, R6, Y1, Y2, Y3, A1, A2, A3, and A4 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprising one or more compounds of formula (I).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation U.S. application Ser. No. 16/254,124,filed Jan. 22, 2019, which is a continuation of U.S. application Ser.No. 16/018,357, filed Jun. 26, 2018, which is a continuation of U.S.application Ser. No. 14/774,866, filed Sep. 11, 2015, now U.S. Pat. No.10,035,800, granted Jul. 31, 2018, which is a National Stage Entry ofInternational PCT Application No. PCT/CN2014/00258, filed on Mar. 12,2014, which claims priority of U.S. Provisional Application 61/928,779,filed Jan. 17, 2014, and U.S. Provisional Application 61/777,797, filedMar. 12, 2013. Each of the foregoing references are incorporated byreference in their entireties.

BACKGROUND

Bromodomains refer to conserved protein structural folds which bind toN-acetylated lysine residues that are found in some proteins. The BETfamily of bromodomain containing proteins is comprised of four members(BRD2, BRD3, BRD4 and BRDt). Each member of the BET family employs twobromodomains to recognize N-acetylated lysine residues found primarily,but not exclusively, on the amino-terminal tails of histone proteins.These interactions modulate gene expression by recruiting transcriptionfactors to specific genome locations within chromatin. For example,histone-bound BRD4 recruits the transcription factor P-TEFb topromoters, resulting in the expression of a subset of genes involved incell cycle progression (Yang et al., Mol. Cell. Biol. 28: 967-976(2008)). BRD2 and BRD3 also function as transcriptional regulators ofgrowth promoting genes (LeRoy et al., Mol. Cell 30: 51-60 (2008)). BETfamily members were recently established as being important for themaintenance of several cancer types (Zuber et al., Nature 478: 524-528(2011); Mertz et al; Proc. Nat'l. Acad. Sci. 108: 16669-16674 (2011);Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478:529-533 (2011)). BET family members have also been implicated inmediating acute inflammatory responses through the canonical NF-KBpathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)) resultingin the upregulation of genes associated with the production of cytokines(Nicodeme et al., Nature 468: 1119-1123, (2010)). Suppression ofcytokine induction by BET bromodomain inhibitors has been shown to be aneffective approach to treat inflammation-mediated kidney disease in ananimal model (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012)).BRD2 function has been linked to predisposition for dyslipidemia orimproper regulation of adipogenesis, elevated inflammatory profiles andincreased susceptibility to autoimmune diseases (Denis, DiscoveryMedicine 10: 489-499 (2010)). The human immunodeficiency virus utilizesBRD4 to initiate transcription of viral RNA from stably integrated viralDNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomaininhibitors have also been shown to reactivate HIV transcription inmodels of latent T cell infection and latent monocyte infection(Banerjee, et al, J. Leukocyte Biol. doi:10.1189/jlb.0312165). BRDt hasan important role in spermatogenesis that is blocked by BET bromodomaininhibitors (Matzuk, et al., Cell 150: 673-684 (2012)). Thus, compoundsthat inhibit the binding of BET family bromodomains to their cognateacetylated lysine proteins are being pursued for the treatment ofcancer, inflammatory diseases, kidney diseases, diseases involvingmetabolism or fat accumulation, and some viral infections, as well asfor providing a method for male contraception. Accordingly, there is anongoing medical need to develop new drugs to treat these indications.

SUMMARY

In one aspect the present invention relates to compounds of formula (I)or a salt thereof,

wherein

-   Y is N or CH;-   R¹ is CD3, C₁-C₃ alkyl, or C₁-C₃ haloalkyl;-   R² is H or C₁-C₃ alkyl;-   Y³ is N or CR³;-   R³ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆    haloalkyl, —CN, —C(O)R^(3a), —C(O)OR^(3a), —C(O)NR^(3b)R^(3c),    —S(O)R^(3d), —S(O)₂R^(3a), —S(O)₂NR^(3b)R^(3c), or G¹; wherein the    C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently    unsubstituted or substituted with 1 or 2 substituents independently    selected from the group consisting of G¹, —CN, —C(O)R^(3a),    —C(O)OR^(3a), —C(O)NR^(3b)R^(3c), —C(O)N(R^(3b))NR^(3b)R^(3c),    —S(O)R^(3d), —S(O)₂R^(3a), —S(O)₂NR^(3b)R^(3c), —OR^(3a),    —OC(O)R^(3d), —NR^(3b)R^(3c), N(R^(3b))C(O)R^(3d),    N(R^(3b))SO₂R^(3d), N(R^(3b))C(O)OR^(3d),    N(R^(3b))C(O)NR^(3b)R^(3c), N(R^(3b))SO₂NR^(3b)R^(3c), and    N(R^(3b))C(NR^(3b)R^(3c))═NR^(3b)R^(3c);-   Y² is C(O), S(O)₂, or CR⁴R⁵;-   R⁴ is H, deuterium, C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl;-   R⁵ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    halogen, C₁-C₆ haloalkyl, —C(O)R^(5a), —C(O)OR^(5a),    —C(O)NR^(5b)R^(5c), —S(O)R^(5d), —S(O)₂R^(5a), —S(O)₂NR^(5b)R^(5c),    or G¹; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are    each independently unsubstituted or substituted with 1 or 2    substituents independently selected from the group consisting of G¹,    —CN, —C(O)R^(5a), —C(O)OR^(5a), —C(O)NR^(5b)R^(5c),    —C(O)N(R^(5b))NR^(5b)R^(5c), —S(O)R^(5d), —S(O)₂R^(5a),    —S(O)₂NR^(5b)R^(5c), —OR^(5a), —OC(O)R^(5d), —NR^(5b)R^(5c),    N(R^(5b))C(O)R^(5d), N(R^(5b))SO₂R^(5d), N(R^(5b))C(O)OR^(5d),    N(R^(5b))C(O)NR^(5b)R^(5c), N(R^(5b))SO₂NR^(5b)R^(5c), and    N(R^(5b))C(NR^(5b)R^(5c))═NR^(5b)R^(5c);-   R^(3a), R^(3b), R^(3c), R^(5a), and R^(5b), at each occurrence, are    each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    C₁-C₆ haloalkyl, G¹, or —(C₁-C₆ alkylenyl)-G¹; R^(5c), at each    occurrence, is independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₁-C₆ haloalkyl, G¹, —(C₁-C₆ alkylenyl)-G¹, —(C₁-C₆    alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(a), or —(C₁-C₆    alkylenyl)-C(O)OR^(a);-   R^(3d), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, or —(C₁-C₆    alkylenyl)-G¹;-   R^(5d), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, —(C₁-C₆ alkylenyl)-G¹,    —(C₁-C₆ alkylenyl)-NR^(c)R^(d), or —(C₁-C₆    alkylenyl)-N(R^(e))C(O)O(R^(b));-   G¹, at each occurrence, is independently aryl, heteroaryl,    heterocycle, cycloalkyl, or cycloalkenyl; and each G¹ is optionally    substituted with 1, 2, 3, 4, or 5 R^(1g) groups;-   R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆    haloalkyl, —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c),    —S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), or G²; wherein the C₁-C₆ alkyl,    C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently    unsubstituted or substituted with 1 or 2 substituents independently    selected from the group consisting of G², —CN, —C(O)R^(6a),    —C(O)OR^(6a), —C(O)NR^(6b)R^(6c), —C(O)N(R^(6b))NR^(6b)R^(6c),    —S(O)R^(6d), —S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), —OR^(6a),    —OC(O)R^(6d), —NR^(6b)R^(6c), N(R^(6b))C(O)R^(6d),    N(R^(6b))SO₂R^(6d), N(R^(6b))C(O)OR^(6d),    N(R^(6b))C(O)NR^(6b)R^(6c), N(R^(6b))SO₂NR^(6b)R^(6c), and    N(R^(6b))C(NR^(6b)R^(6c))═NR^(6b)R^(6c);-   R^(6a), R^(6b), and R^(6c), at each occurrence, are each    independently H, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G²,    —(C₁-C₆ alkylenyl)-G², —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆    alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆    alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆    alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆    alkylenyl)-N(Re)C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),    —(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆    alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);-   R^(6d), at each occurrence, is independently alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, haloalkyl, G², —(C₁-C₆ alkylenyl)-G², —(C₁-C₆    alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆    alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆    alkylenyl)-C(O)OR^(a), —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆    alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b),    —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆    alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);-   G², at each occurrence, is independently aryl, heteroaryl,    heterocycle, cycloalkyl, or cycloalkenyl; and each G² is optionally    substituted with 1, 2, 3, 4, or 5 R^(2g) groups;-   A¹ is C(R⁷) or N; A² is C(R⁸) or N; A³ is C(R⁹) or N; and A⁴ is    C(R¹⁰) or N; wherein zero, one, or two of A¹, A², A³, and A⁴ are N;-   R⁷, R⁸, and R⁹, are each independently H, C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂,    —OR^(y1), —OC(O)R^(y2), —OC(O)NR^(y3)R^(y4), —SR^(y1), —S(O)₂R^(y1),    —S(O)₂NR^(y3)R^(y4), —C(O)R^(y1), —C(O)OR^(y1), —C(O)NR^(y3)R^(y4),    —NR^(y3)R^(y4), —N(R^(y3))C(O)R^(y2), —N(R^(y3))S(O)₂R^(y2),    —N(R^(y3))C(O)O(R^(y2)), —N(R^(y3))C(O)NR^(y3)R^(y4),    —N(R^(y3))S(O)₂NR^(y3)R^(y4), G³, —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆    alkylenyl)-OR^(y1), —(C₁-C₆ alkylenyl)-OC(O)R^(y2), —(C₁-C₆    alkylenyl)-OC(O)NR³R^(y4), —(C₁-C₆ alkylenyl)-S(O)₂R^(y1), —(C₁-C₆    alkylenyl)-S(O)₂NR³R^(y4), —(C₁-C₆ alkylenyl)-C(O)R^(y1), —(C₁-C₆    alkylenyl)-C(O)OR^(y1), —(C₁-C₆ alkylenyl)-C(O)NR³R⁴, —(C₁-C₆    alkylenyl)-NR³R^(y4), —(C₁-C₆ alkylenyl)-N(R³)C(O)R^(y2), —(C₁-C₆    alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆    alkylenyl)-N(R^(y3))C(O)O(R^(y2)), —(C₁-C₆    alkylenyl)-N(R³)C(O)NR^(y3)R^(y4), —(C₁-C₆    alkylenyl)-N(R³)S(O)₂NR³R^(y4), —(C₁-C₆ alkylenyl)-CN, or —(C₁-C₆    alkylenyl)-G³; R^(y1), R^(y3), and R^(y4), at each occurrence, are    each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    C₁-C₆ haloalkyl, G³, —(C₁-C₆ alkylenyl)-G³, —(C₁-C₆    alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆    alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆    alkylenyl)-C(O)OR^(a), —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆    alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b),    —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆    alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); R^(y2), at each occurrence, is    independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆    haloalkyl, G³, —(C₁-C₆ alkylenyl)-G³, —(C₁-C₆ alkylenyl)-OR^(a),    —(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d),    —(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆    alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),    —(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆    alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);-   G³, at each occurrence, is independently aryl, heteroaryl,    cycloalkyl, cycloalkenyl, or heterocycle; and each G³ group is    optionally substituted with 1, 2, 3, 4, or 5 R^(4g) groups;-   R¹⁰ is H, C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, or —CN; R^(1g),    R^(2g), and R^(4g), at each occurrence, is independently selected    from the group consisting of oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, G^(2a), —OR^(a),    —OC(O)R^(b), —OC(O)NR^(c)R^(d), —SR^(a), —S(O)₂R^(a),    —S(O)₂NR^(c)R^(d), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(d),    —NR^(c)R^(d), —N(R^(e))C(O)R^(b), —N(R^(e))S(O)₂R^(b),    —N(R^(e))C(O)O(R^(b)), —N(R^(e))C(O)NR^(c)R^(d),    —N(R^(e))S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆    alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆    alkylenyl)-OC(O)R^(b), —(C₁-C₆ alkylenyl)-OC(O)NR^(c)R^(d), —(C₁-C₆    alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆    alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆    alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),    —(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), —(C₁-C₆    alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d), or —(C₁-C₆ alkylenyl)-CN;-   R^(a), R^(c), R^(d), and R^(e), at each occurrence, are each    independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆    haloalkyl, G^(2a), —(C₁-C₆ alkylenyl)-OR^(z1), —(C₁-C₆    alkylenyl)-NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-C(O)NR^(z3)R^(z4), or    —(C₁-C₆ alkylenyl)-G²a;-   R^(b), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2a), or —(C₁-C₆    alkylenyl)-G^(2a);-   G^(2a), at each occurrence, are each independently aryl, heteroaryl,    heterocycle, cycloalkyl, or cycloalkenyl; and each G^(2a) group is    optionally substituted with 1, 2, 3, 4, or 5 R^(3g) groups;-   R^(3g), at each occurrence, is independently oxo, C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂,    —OR^(z1), —OC(O)R^(z2), —OC(O)NR^(z3)R^(z4), —SR^(z1), —S(O)₂R^(z1),    —S(O)₂NR^(z3)R^(z4), —C(O)R^(z1), —C(O)OR^(z1), —C(O)NR^(z3)R^(z4),    —NR^(z3)R^(z4), —N(R^(z3))C(O)R², —N(R^(z3))S(O)₂R^(z2),    —N(R^(z3))C(O)O(R^(z2)), —N(R^(z3))C(O)NR^(z3)R^(z4),    —N(R^(z3))S(O)₂NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-OR^(z1), —(C₁-C₆    alkylenyl)-OC(O)R^(z2), —(C₁-C₆ alkylenyl)-OC(O)NR^(z3)R^(z4),    —(C₁-C₆ alkylenyl)-S(O)₂R^(z), —(C₁-C₆    alkylenyl)-S(O)₂NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-C(O)R^(z1),    —(C₁-C₆ alkylenyl)-C(O)OR^(z), —(C₁-C₆ alkylenyl)-C(O)NR^(z3)R^(z4),    —(C₁-C₆ alkylenyl)-NR^(z3)R^(z4), —(C₁-C₆    alkylenyl)-N(R^(z3))C(O)R^(z2), —(C₁-C₆    alkylenyl)-N(R^(z3))S(O)₂R^(z2), —(C₁-C₆    alkylenyl)-N(R^(z3))C(O)O(R^(z2)), —(C₁-C₆    alkylenyl)-N(R^(z3))C(O)NR³R⁴, —(C₁-C₆    alkylenyl)-N(R^(z3))S(O)₂NR^(z3)R^(z4), or —(C₁-C₆ alkylenyl)-CN;-   R^(z1), R^(z3), and R^(z4), at each occurrence, are each    independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆    haloalkyl; and-   R^(z2), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl.

In another aspect, the present invention provides for methods fortreating or preventing disorders that are ameliorated by inhibition ofBET. Such methods comprise of administering to the subject atherapeutically effective amount of a compound of formula (I), alone, orin combination with a pharmaceutically acceptable carrier.

Some of the methods are directed to treating or preventing aninflammatory disease or cancer or AIDS.

In another aspect, the present invention relates to methods of treatingcancer in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In certain embodiments, thecancer is selected from the group consisting of: acoustic neuroma, acuteleukemia, acute lymphocytic leukemia, acute myelocytic leukemia(monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma,myelomonocytic and promyelocytic), acute t-cell leukemia, basal cellcarcinoma, bile duct carcinoma, bladder cancer, brain cancer, breastcancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma,chordoma, choriocarcinoma, chronic leukemia, chronic lymphocyticleukemia, chronic myelocytic (granulocytic) leukemia, chronicmyelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor. In certain embodiments, the methods further compriseadministering a therapeutically effective amount of at least oneadditional therapeutic agent. In certain embodiments, the additionaltherapeutic agent is selected from the group consisting of cytarabine,bortezomib, and 5-azacitidine.

In another aspect, the present invention relates to methods of treatinga disease or condition in a subject comprising administering atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof, to a subject in need thereof,wherein said disease or condition is selected from the group consistingof: Addison's disease, acute gout, ankylosing spondylitis, asthma,atherosclerosis, Behcet's disease, bullous skin diseases, cardiacmyopathy, cardiac hypertrophy, chronic obstructive pulmonary disease(COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis,glomerulonephritis, heart failure, hepatitis, hypophysitis, inflammatorybowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis,myocarditis, myositis, nephritis, organ transplant rejection,osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa,pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis,rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis,systemic lupus erythematosus, Takayasu's Arteritis, toxic shock,thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo,vasculitis, and Wegener's granulomatosis. In certain embodiments, themethods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatinga chronic kidney disease or condition in a subject comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said disease or condition is selected from thegroup consisting of: diabetic nephropathy, hypertensive nephropathy,HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgAnephropathy, focal segmental glomerulosclerosis, membranousglomerulonephritis, minimal change disease, polycystic kidney diseaseand tubular interstitial nephritis. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingan acute kidney injury or disease or condition in a subject comprisingadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said acute kidney injury or disease orcondition is selected from the group consisting of: ischemia-reperfusioninduced kidney disease, cardiac and major surgery induced kidneydisease, percutaneous coronary intervention induced kidney disease,radio-contrast agent induced kidney disease, sepsis induced kidneydisease, pneumonia induced kidney disease, and drug toxicity inducedkidney disease. In certain embodiments, the methods further compriseadministering a therapeutically effective amount of at least oneadditional therapeutic agent.

In another aspect, the present invention relates to methods of treatingAIDS in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In certain embodiments, themethods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent.

In another aspect, the present invention relates to methods of treatingobesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease,metabolic syndrome, hepatic steatosis, type II diabetes, insulinresistance, diabetic retinopathy or diabetic neuropathy in a subjectcomprising administering a therapeutically effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof,to a subject in need thereof. In certain embodiments, the methodsfurther comprise administering a therapeutically effective amount of atleast one additional therapeutic agent.

In another aspect, the present invention provides for contraception in amale subject comprising administering a therapeutically effective amountof a compound of formula (I), or a pharmaceutically acceptable saltthereof, to a subject in need thereof. In certain embodiments, themethods further comprise administering a therapeutically effectiveamount of at least one additional therapeutic agent.

A further aspect of the invention provides the use of a compound offormula (I), alone or in combination with a second active pharmaceuticalagent, in the manufacture of a medicament for treating or preventingconditions and disorders disclosed herein, with or without apharmaceutically acceptable carrier.

Pharmaceutical compositions comprising a compound of formula (I), or apharmaceutically acceptable salt, alone or in combination with a secondactive pharmaceutical agent, are also provided. In certain embodiments,pharmaceutical compositions comprise a therapeutically effective amountof a compound of formula (I), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

Disclosed herein are compounds of formula (I)

wherein R¹, R², R⁶, Y¹, Y², Y³, A¹, A², A³, and A⁴ are defined above inthe Summary of the Invention and below in the Detailed Description.Further, compositions comprising such compounds and methods for treatingconditions and disorders using such compounds and compositions are alsodisclosed.

Compounds disclosed herein may contain one or more variable(s) thatoccur more than one time in any substituent or in the formulae herein.Definition of a variable on each occurrence is independent of itsdefinition at another occurrence. Further, combinations of substituentsare permissible only if such combinations result in stable compounds.Stable compounds are compounds, which can be isolated from a reactionmixture.

a). Definitions

It is noted that, as used in this specification and the intended claims,the singular form “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a compound” includes a single compound as well as one or more of thesame or different compounds, reference to “optionally a pharmaceuticallyacceptable carrier” refers to a single optional pharmaceuticallyacceptable carrier as well as one or more pharmaceutically acceptablecarriers, and the like.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond, optionally substituted with 1, 2,or 3 halogen atoms. The term “C₂-C₆ alkenyl” means an alkenyl groupcontaining 2-6 carbon atoms. Non-limiting examples of alkenyl includebuta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of 2 to 4 carbon atoms and contains at leastone carbon-carbon double bond. Representative examples of alkenyleneinclude, but are not limited to, —CH═CH— and —CH₂CH═CH—.

The term “alkyl” as used herein, means a saturated, straight or branchedhydrocarbon chain radical. In some instances, the number of carbon atomsin an alkyl moiety is indicated by the prefix “C_(x)-C_(y)”, wherein xis the minimum and y is the maximum number of carbon atoms in thesubstituent. Thus, for example, “C₁-C₆ alkyl” refers to an alkylsubstituent containing from 1 to 6 carbon atoms and “C₁-C₃ alkyl” refersto an alkyl substituent containing from 1 to 3 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl,1-ethylpropyl, 1,2,2-trimethylpropyl, 2-ethylhexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylene” or “alkylenyl” means a divalent radical derived froma straight or branched, saturated hydrocarbon chain, for example, of 1to 10 carbon atoms or of 1 to 6 carbon atoms (C₁-C₆ alkylenyl) or of 1to 4 carbon atoms or of 2 to 3 carbon atoms (C₂-C₃ alkylenyl). Examplesof alkylene and alkylenyl include, but are not limited to, —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon radical containing from 2 to 10 carbon atoms and containingat least one carbon-carbon triple bond, optionally substituted with 1,2, or 3 halogen atoms. The term “C₂-C₆ alkynyl” means an alkynyl groupof 2 to 6 carbon atoms. Representative examples of alkynyl include, butare not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl,2-pentynyl, 1-butynyl, and but-2-yn-1-yl.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. Thebicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl,or a phenyl fused to a monocyclic cycloalkenyl. Non-limiting examples ofthe aryl groups include dihydroindenyl (indanyl), indenyl, naphthyl,dihydronaphthalenyl, and tetrahydronaphthalenyl. The aryls are attachedto the parent molecular moiety through any carbon atom contained withinthe bicyclic ring systems and can be unsubstituted or substituted.

The term “cycloalkyl” as used herein, refers to a radical that is amonocyclic cyclic alkyl, a bicyclic cycloalkyl, or a spiro cycloalkyl. Amonocyclic cycloalkyl is a carbocyclic ring system containing three toeight carbon atoms, zero heteroatoms and zero double bonds, i.e., aC₃-C₈ cycloalkyl. In certain embodiments, a cycloalkyl refers to amonocyclic C₃-C₇ cycloalkyl. Examples of monocyclic ring systems includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. A bicyclic cycloalkyl is a monocyclic cycloalkyl fused to amonocyclic cycloalkyl ring. Monocyclic and the bicyclic cycloalkylgroups may contain one or two alkylene bridges, each consisting of one,two, three, or four carbon atoms in length, and each bridge links twonon-adjacent carbon atoms of the ring system. Non-limiting examples ofbicyclic ring systems include bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane,tricyclo[3.3.1.0^(3,7)]nonane (octahydro-2,5-methanopentalene ornoradamantane), and tricyclo[3.3.1.1^(3,7)]decane (adamantane). A spirocycloalkyl is a monocyclic cycloalkyl wherein two substituents on thesame carbon atom of the monocyclic cycloalkyl ring together with saidcarbon atom form a second monocyclic cycloalkyl ring. Monocyclic, thebicyclic, and the spiro cycloalkyl groups can be unsubstituted orsubstituted, and are attached to the parent molecular moiety through anysubstitutable atom contained within the ring system.

The term “cycloalkenyl” as used herein, refers to a monocyclic or abicyclic hydrocarbon ring radical. A monocyclic cycloalkenyl has four-,five-, six-, seven- or eight carbon atoms and zero heteroatoms, i.e., aC₄-C₈ cycloalkenyl. The four-membered ring systems have one double bond,the five- or six-membered ring systems have one or two double bonds, andthe seven- or eight-membered ring systems have one, two, or three doublebonds. Representative examples of monocyclic cycloalkenyl groupsinclude, but are not limited to, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, and cyclooctenyl. A bicyclic cycloalkenylis a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, ora monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group.Monocyclic or bicyclic cycloalkenyl ring may contain one or two alkylenebridges, each consisting of one, two, or three carbon atoms, and eachlinking two non-adjacent carbon atoms of the ring system. Representativeexamples of the bicyclic cycloalkenyl groups include, but are notlimited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl, and1,6-dihydro-pentalene.

Monocyclic and bicyclic cycloalkenyls can be attached to the parentmolecular moiety through any substitutable atom contained within thering systems, and can be unsubstituted or substituted.

The term “halo” or “halogen” as used herein, means Cl, Br, I, and F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. The term “C₁-C₆ haloalkyl” means a C₁-C₆ alkylgroup, as defined herein, in which one, two, three, four, five, six, orseven hydrogen atoms are replaced by halogen. The term “C₁-C₃ haloalkyl”means a C₁-C₃ alkyl group, as defined herein, in which one, two, three,four, five, or six hydrogen atoms are replaced by halogen.Representative examples of haloalkyl include, but are not limited to,chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,trifluoromethyl, difluoromethyl, pentafluoroethyl, 4-chlorobutyl,2-chloro-3-fluoropentyl, trifluorobutyl, trifluoropropyl,2,2,3,3,3-pentafluoropropyl, and 2,2,3,3,4,4,4-heptafluorobutyl.

The term “heterocycle” or “heterocyclic” as used herein, means a radicalof a monocyclic heterocycle, a bicyclic heterocycle, and a spiroheterocycle. A monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered carbocyclic ring also containing at least oneheteroatom independently selected from the group consisting of O, N, andS. A three- or four-membered ring contains zero or one double bond, andone heteroatom selected from the group consisting of O, N, and S. Whentwo O atoms or one O atom and one S atom are present in a heterocyclicring, then the two O atoms or one O atom and one S atom are not bondeddirectly to each other. A five-membered ring contains zero or one doublebond and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Examples of five-membered heterocyclic ringsinclude those containing in the ring: 1 O; 1 S; 1N; 2N; 3N; 1 S and N; 1S, and 2N; 1 O and 1 N; or 1 O and 2N. Examples of 5-memberedheterocyclic groups include tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl,imidazolinyl, isoxazolidinyl, pyrrolidinyl, 2-pyrrolinyl, and3-pyrrolinyl. A six-membered ring contains zero, one, or two doublebonds and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Examples of six-membered heterocyclic ringsinclude those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1N; 2 N; 3 N;1 S, 10, and 1N; 1 S and 1N; 1 S and 2N; 1 S and 1 O; 1 S and 2 O; 1 Qand 1 N; and 1 O and 2 N. Examples of 6-membered heterocyclic groupsinclude tetrahydropyranyl, dihydropyranyl, dioxanyl, 1,3-dioxolanyl,1,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl,piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl,1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl,1,1-dioxo-hexahydro-1-thiopyranyl, 1,1-dioxo-1λ⁶-thiomorpholinyl,thiomorpholinyl, thioxanyl, and trithianyl. Seven- and eight-memberedrings contains zero, one, two, or three double bonds and one, two, orthree heteroatoms selected from the group consisting of O, N, and S.Representative examples of monocyclic heterocycles include, but are notlimited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl,thiomorpholinyl, thiopyranyl, and trithianyl. The bicyclic heterocycleis a monocyclic heterocycle fused to a phenyl group, or a monocyclicheterocycle fused to a monocyclic cycloalkyl, or a monocyclicheterocycle fused to a monocyclic cycloalkenyl, or a monocyclicheterocycle fused to a monocyclic heterocycle. Representative examplesof bicyclic heterocycles include, but are not limited to,1,3-benzodioxolyl, benzopyranyl, benzothiopyranyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydro-1H-indolyl, dihydroisoindol-2-yl, isoindolinyl,3,4-dihydroisoquinolin-2(1H)-yl,2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl,hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl. The monocyclic heterocycleand the bicyclic heterocycle may contain one or two alkylene bridges oran alkenylene bridge, or mixture thereof, each consisting of no morethan four carbon atoms and each linking two non adjacent atoms of thering system. Examples of such bridged heterocycle include, but are notlimited to, azabicyclo[2.2.1]heptyl (including2-azabicyclo[2.2.1]hept-2-yl), 8-azabicyclo[3.2.1]oct-8-yl,octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). A spiro heterocycle is amonocyclic heterocycle wherein two substituents on the same carbon atomof the monocyclic heterocycle ring together with said carbon atom form asecond ring system selected from a monocyclic cycloalkyl, a bicycliccycloalkyl, a monocyclic heterocycle, or a bicyclic heterocycle.Examples of spiro heterocycle include, but not limited to,6-azaspiro[2.5]oct-6-yl, 1′H,4H-spiro[1,3-benzodioxine-2,4′-piperidin]-1′-yl, 1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl, and1,4-dioxa-8-azaspiro[4.5]dec-8-yl. The monocyclic, the bicyclic, and thespiro heterocycles can be unsubstituted or substituted. The monocyclic,the bicyclic and the spiro heterocycles are connected to the parentmolecular moiety through any carbon atom or any nitrogen atom containedwithin the ring systems.

The nitrogen and sulfur heteroatoms in the heterocycle rings mayoptionally be oxidized (e.g. 1,1-dioxidotetrahydrothienyl,1,2-dioxido-1,2-thiazolidinyl, 1,1-dioxidothiomorpholinyl)) and thenitrogen atoms may optionally be quarternized.

The term “C₄-C₆ heterocycle” or “C₄-C₆ heterocyclic” as used herein,means a 4, 5, or 6 membered monocyclic heterocycle as defined hereinabove. Non-limiting examples of C₄-C₆ heterocycle include azetidinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl,piperidinyl, and morpholinyl.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl anda bicyclic heteroaryl. The monocyclic heteroaryl is a five- orsix-membered monocyclic ring. The five-membered ring contains two doublebonds. The five membered ring may contain one heteroatom selected from Oor S; or one, two, three, or four nitrogen atoms and optionally oneoxygen or one sulfur atom. The six-membered ring contains three doublebonds and one, two, three or four nitrogen atoms. Representativeexamples of monocyclic heteroaryl include, but are not limited to,furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl,and triazinyl. The bicyclic heteroaryl consists of a monocyclicheteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to amonocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocycliccycloalkenyl, or a monocyclic heteroaryl fused to a monocyclicheteroaryl, or a monocyclic heteroaryl fused to a monocyclicheterocycle. Representative examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl,2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl,quinolinyl, 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroarylgroups can be substituted or unsubstituted and are connected to theparent molecular moiety through any substitutable carbon atom or anysubstitutable nitrogen atom contained within the ring systems. Thenitrogen atom in the heteroaryl rings may optionally be oxidized and mayoptionally be quarternized.

The term “heteroatom” as used herein, means a nitrogen, oxygen, andsulfur.

The term “oxo” as used herein, means a ═O group.

If a moiety is described as “substituted”, a non-hydrogen radical is inthe place of hydrogen radical of any substitutable atom of the moiety.Thus, for example, a substituted heterocycle moiety is a heterocyclemoiety in which at least one non-hydrogen radical is in the place of ahydrogen radical on the heterocycle. It should be recognized that ifthere are more than one substitution on a moiety, each non-hydrogenradical may be identical or different (unless otherwise stated).

If a moiety is described as being “optionally substituted,” the moietymay be either (1) not substituted or (2) substituted. If a moiety isdescribed as being optionally substituted with up to a particular numberof non-hydrogen radicals, that moiety may be either (1) not substituted;or (2) substituted by up to that particular number of non-hydrogenradicals or by up to the maximum number of substitutable positions onthe moiety, whichever is less. Thus, for example, if a moiety isdescribed as a heteroaryl optionally substituted with up to 3non-hydrogen radicals, then any heteroaryl with less than 3substitutable positions would be optionally substituted by up to only asmany non-hydrogen radicals as the heteroaryl has substitutablepositions. To illustrate, tetrazolyl (which has only one substitutableposition) would be optionally substituted with up to one non-hydrogenradical. To illustrate further, if an amino nitrogen is described asbeing optionally substituted with up to 2 non-hydrogen radicals, then aprimary amino nitrogen will be optionally substituted with up to 2non-hydrogen radicals, whereas a secondary amino nitrogen will beoptionally substituted with up to only 1 non-hydrogen radical.

The terms “treat”, “treating”, and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing”, and “prevention” refer to a method ofpreventing the onset of a disease and/or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease and/or its attendant symptoms and reducing a subject's risk ofacquiring a disease.

The phrase “therapeutically effective amount” means an amount of acompound, or a pharmaceutically acceptable salt thereof, sufficient toprevent the development of or to alleviate to some extent one or more ofthe symptoms of the condition or disorder being treated whenadministered alone or in conjunction with another pharmaceutical agentor treatment in a particular subject or subject population. For examplein a human or other mammal, a therapeutically effective amount can bedetermined experimentally in a laboratory or clinical setting, or may bethe amount required by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular diseaseand subject being treated.

The term “subject” is defined herein to refer to animals such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

b. Compounds

Compounds of the invention have the general formula (I) as describedabove.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values may be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

In certain embodiments of formula (I), Y¹ is N or CH.

In certain embodiments, Y¹ is N.

In certain embodiments, Y¹ is CH.

In certain embodiments of formula (I), R¹ is CD3, C₁-C₃ alkyl, or C₁-C₃haloalkyl.

In certain embodiments, R¹ is C₁-C₃ alkyl. In some such embodiments, R¹is methyl.

In certain embodiments of formula (I), R² is H or C₁-C₃ alkyl.

In certain embodiments, R² is H or methyl.

In certain embodiments, R² is H.

In certain embodiments, R² is C₁-C₃ alkyl. In some such embodiments, R²is methyl.

In certain embodiments of formula (I), Y³ is N or CR³.

In certain embodiments, Y³ is N.

In certain embodiments, Y³ is CR³.

In certain embodiments of formula (I), R³ is H, —CN, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —C(O)R^(3a),—C(O)OR^(3a), —C(O)NR^(3b)R^(3c), —S(O)R^(3d), —S(O)₂R^(3a),—S(O)₂NR^(3b)R^(3c), or G¹; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, andC₂-C₆ alkynyl are each independently unsubstituted or substituted with 1or 2 substituents independently selected from the group consisting ofG¹, —CN, —C(O)R^(3a), —C(O)OR^(3a), —C(O)NR^(3b)R^(3c),—C(O)N(R^(3b))NR^(3b)R^(3c), —S(O)R^(3d), —S(O)₂R^(3a),—S(O)₂NR^(3b)R^(3c), —OR^(3a), —OC(O)R^(3d), —NR^(3b)R^(3c),N(R^(3b))C(O)R^(3d), N(R^(3b))SO₂R^(3d), N(R^(3b))C(O)OR^(3d),N(R^(3b))C(O)NR^(3b)R^(3c), N(R^(3b))SO₂NR^(3b)R^(3c) andN(R^(3b))C(NR^(3b)R^(3c))═NR^(3b)R^(3c).

In certain embodiments, R³ is H, —CN, —C(O)R^(3a), —C(O)OR^(3a),—C(O)NR^(3b)R^(3c), or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl isoptionally substituted with a substituent selected from the groupconsisting of G¹, —NR^(3b)R^(3c), N(R^(3b))C(O)R^(3d),N(R^(3b))SO₂R^(3d), N(R^(3b))C(O)OR^(3d), N(R^(3b))C(O)NR^(3b)R^(3c),and N(R^(3b))SO₂NR^(3b)R^(3c). In some such embodiments, the G¹ group isoptionally substituted heterocycle. In some such embodiments, the C₁-C₆alkyl is substituted with a G¹ group, wherein the G¹ group ispiperidinyl, piperazinyl, or morpholinyl, each of which is optionallysubstituted with 1 or 2 C₁-C₆ alkyl. In some such embodiments, the C₁-C₆alkyl is substituted with a G¹ group, wherein the G¹ group ispiperazinyl or morpholinyl, each of which is optionally substituted with1 or 2 C₁-C₆ alkyl.

In certain embodiments, R³ is H, —C(O)NR^(3b)R^(3c), —CN, or C₁-C₆ alkylwhich is substituted with a G¹ group. In some such embodiments, theC₁-C₆ alkyl is substituted with a G¹ group, wherein the G¹ group is anoptionally substituted C₄-C₆ heterocycle. In some such embodiments, theC₁-C₆ alkyl is substituted with a G¹ group, wherein the G¹ group ispiperidinyl, piperazinyl, or morpholinyl, each of which is optionallysubstituted with 1 or 2 C₁-C₆ alkyl.

In certain embodiments, R³ is H, —C(O)R^(3a), or —C(O)NR^(3b)R^(3c). Insome such embodiments, R^(3a) is G¹. In some such embodiments, R^(3a) isG¹ wherein G¹ is optionally substituted heterocycle. In some suchembodiments, R^(3a) is G¹ wherein G¹ is piperidinyl, piperazinyl, ormorpholinyl, each of which is optionally substituted with 1 or 2 C₁-C₆alkyl. In some such embodiments, R^(3a) is G¹ wherein G¹ is piperazinyl,optionally substituted with 1 or 2 C₁-C₆ alkyl.

In certain embodiments, R³ is H or —C(O)NR^(3b)R^(3c). In some suchembodiments, R^(3b) and R^(3c) are each independently H or C₁-C₆ alkyl.

In certain embodiments, R³ is H.

In certain embodiments, R³ is —C(O)NR^(3b)R^(3c). In some suchembodiments, R^(3b) and R^(3c) are each independently H or C₁-C₃ alkyl.

In certain embodiments, R³ is G¹. In some such embodiments, G¹ isoptionally substituted monocyclic heteroaryl. In some such embodiments,G¹ is optionally substituted pyrazolyl. In some such embodiments, G¹ ispyrazolyl substituted with 1 or 2 C₁-C₆ alkyl.

In certain embodiments of formula (I), Y² is C(O), S(O)₂, or CR⁴R⁵.

In certain embodiments, Y² is C(O).

In certain embodiments, Y² is S(O)₂.

In certain embodiments, Y² is CR⁴R⁵.

In certain embodiments of formula (I), R⁴ is H, deuterium, C₁-C₆ alkyl,halogen, or C₁-C₆ haloalkyl.

In certain embodiments, R⁴ is H or deuterium.

In certain embodiments, R⁴ is H.

In certain embodiments of formula (I), R⁵ is H, deuterium, C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —C(O)R^(5a),—C(O)OR^(5a), —C(O)NR^(5b)R^(5c), —S(O)R^(5d), —S(O)₂R^(5a),—S(O)₂NR^(5b)R^(5c), or G¹; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, andC₂-C₆ alkynyl are each independently unsubstituted or substituted with 1or 2 substituents independently selected from the group consisting ofG¹, —CN, —C(O)R^(5a), —C(O)OR^(5a), —C(O)NR^(5b)R^(5c),—C(O)N(R^(5b))NR^(5b)R^(5c), —S(O)R^(5d), —S(O)₂R^(5a),—S(O)₂NR^(5b)R^(5c), —OR^(5a), —OC(O)R^(5d), —NR^(5b)R^(5c),N(R^(5b))C(O)R^(5d), N(R^(5b))SO₂R^(5d), N(R^(5b))C(O)OR^(5d),N(R^(5b))C(O)NR^(5b)R^(5c), N(R^(5b))SO₂NR^(5b)R^(5c), andN(R^(5b))C(NR^(5b)R^(5c))═NR^(5b)R^(5c).

In certain embodiments, R⁵ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ haloalkyl, —C(O)R^(5a), —C(O)OR^(5a), or G¹;wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are eachindependently unsubstituted or substituted with 1 or 2 substituentsindependently selected from the group consisting of G¹, —C(O)R^(5a),—C(O)OR^(5a), —C(O)NR^(5b)R^(5c), —C(O)N(R^(5b))NR^(5b)R^(5c), —OR^(5a),—OC(O)R^(5d), —NR^(5b)R^(5c), N(R^(5b))C(O)R^(5d), N(R^(5b))SO₂R^(5d),N(R^(5b))C(O)OR^(5d), N(R^(5b))C(O)NR^(5b)R^(5c), andN(R^(5b))SO₂NR^(5b)R^(5c).

In certain embodiments, R⁵ is C₂-C₆ alkenyl optionally substituted witha G¹ group, or R⁵ is H, deuterium, C₁-C₆ alkyl, —C(O)R^(5a),—C(O)OR^(5a), or G¹; wherein the C₁-C₆ alkyl is unsubstituted orsubstituted with a substituent selected from the group consisting of G¹,—C(O)R^(5a), —C(O)OR^(5a), —C(O)NR^(5b)R^(5c),—C(O)N(R^(5b))NR^(5b)R^(5c), —OR^(5a), —OC(O)R^(5d), —NR^(5b)R^(5c), andN(R^(5b))C(NR^(5b)R^(5c))═NR^(5b)R^(5c).

In certain embodiments, R⁵ is H, deuterium, or C₁-C₆ alkyl optionallysubstituted with a substituent selected from the group consisting of—C(O)OR^(5a) and OR^(5a). In some such embodiments, R^(5a) is C₁-C₆alkyl.

In certain embodiments, R⁵ is H.

In certain embodiments of formula (I), R⁶ is H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —C(O)R^(6a),—C(O)OR^(6a), —C(O)NR^(6b)R^(6c), —S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), orG²; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are eachindependently unsubstituted or substituted with 1 or 2 substituentsindependently selected from the group consisting of G², —CN,—C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c),—C(O)N(R^(6b))NR^(6b)R^(6c), —S(O)R^(6d), —S(O)₂R^(6a),—S(O)₂NR^(6b)R^(6c), —OR^(6a), —OC(O)R^(6d), —NR^(6b)R^(6c),N(R^(6b))C(O)R^(6d), N(R^(6b))SO₂R^(6d), N(R^(6b))C(O)OR^(6d),N(R^(6b))C(O)NR^(6b)R^(6c), N(R^(6b))SO₂NR^(6b)R^(6c), andN(R^(6b))C(NR^(6b)R^(6c))═NR^(6b)R^(6c).

In certain embodiments, R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl,—C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c), —S(O)₂R^(6a), or G²;wherein the C₁-C₆ alkyl and the C₂-C₆ alkenyl are each independentlyunsubstituted or substituted with 1 or 2 substituents independentlyselected from the group consisting of G², —CN, —C(O)OR^(6a),—NR^(6b)R^(6c), N(R^(6b))C(O)R^(6d), N(R^(6b))SO₂R^(6d),N(R^(6b))C(O)OR^(6d), N(R^(6b))C(O)NR^(6b)R^(6c), andN(R^(6b))SO₂NR^(6b)R^(6c).

In certain embodiments, R⁶ is H, C₁-C₆ alkyl, —C(O)R^(6a), —C(O)OR^(6a),—C(O)NR^(6b)R^(6c), —S(O)₂R^(6a), or G²; wherein the C₁-C₆ alkyl isunsubstituted or substituted with a substituent selected from the groupconsisting of G² and —C(O)OR^(6a).

In certain embodiments, R⁶ is —C(O)R^(6a), —C(O)OR^(6a),—C(O)NR^(6b)R^(6c), G², or C₁-C₆ alkyl which is unsubstituted orsubstituted with a G² group. In certain embodiments, R^(6a) is G² orunsubstituted C₁-C₆ alkyl.

In certain embodiments, R⁶ is —C(O)OR^(6a). In some such embodiments,R^(6a) is C₁-C₆ alkyl.

In certain embodiments, R⁶ is G² or C₁-C₆ alkyl which is unsubstitutedor substituted with a G² group. In some such embodiments, R⁶ isoptionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocycle, or optionally substitutedcycloalkyl; or R⁶ is C₁-C₆ alkyl which is unsubstituted or substitutedwith a substituent selected from the group consisting of heteroaryl,cycloalkyl, and heterocycle, each of which is optionally substituted. Insome such embodiments, R⁶ is optionally substituted aryl, optionallysubstituted heteroaryl, or optionally substituted cycloalkyl; or R⁶ isC₁-C₆ alkyl which is unsubstituted or substituted with a substituentselected from the group consisting of cycloalkyl and heterocycle, eachof which is optionally substituted. In some such embodiments, R⁶ isphenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indazolyl,cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl,piperidinyl, or azepanyl, each of which is optionally substituted; or R⁶is C₁-C₆ alkyl which is unsubstituted or substituted with a G¹ groupwherein the G¹ group is cyclopropyl, cyclohexyl, pyrrolidinyl,piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1, 3dioxolyl, or pyrazolyl, each of which is optionally substituted. In somesuch embodiments, R⁶ is optionally substituted phenyl, optionallysubstituted pyridinyl, or optionally substituted cyclohexyl; or R⁶ isC₁-C₆ alkyl which is unsubstituted or substituted with a substituentselected from the group consisting of cyclopropyl and tetrahydrofuranyl,each of which is optionally substituted. In some such embodiments, saidoptional substituents are independently selected from the groupconsisting of halogen, —O(C₁-C₃ alkyl), —O(C₁-C₃ haloalkyl),—N(H)C(O)O(C₁-C₆ alkyl), C₁-C₃ alkyl, and C₁-C₃ haloalkyl. In some suchembodiments, said optional substituents are halogen. In some suchembodiments, said halogen is F or C₁.

In certain embodiments of formula (I), A¹ is C(R⁷) or N; A² is C(R⁸) orN; A³ is C(R⁹) or N; and A⁴ is C(R¹⁰) or N; wherein zero, one, or two ofA¹, A², A³, and A⁴ are N.

In certain embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ isC(R¹⁰).

In certain embodiments, one of A¹, A², A³, and A⁴ is N. In some suchembodiments, A¹ is N; A² is C(R⁸); A³ is C(R⁹); and A⁴ is C(R¹⁰).

In certain embodiments, two of A¹, A², A³, and A⁴ are N. In some suchembodiments, A¹ is N; A² is C(R⁸); A³ is N; and A⁴ is C(R¹⁰).

In certain embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ isC(R¹⁰); or A¹ is N; A² is C(R⁸); A³ is C(R⁹); and A⁴ is C(R¹⁰); or A¹ isN; A² is C(R⁸); A³ is N; and A⁴ is C(R¹⁰).

In certain embodiments of formula (I), R⁷, R⁸, and R⁹, are eachindependently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen,C₁-C₆ haloalkyl, —CN, NO₂, —OR^(y1), —OC(O)R^(y2), —OC(O)NR^(y3)R^(y4),—SR^(y1), —S(O)₂R^(y1), —S(O)₂NR^(y3)R^(y4), —C(O)R^(y1), —C(O)OR^(y1),—C(O)NR^(y3)R^(y4), —NR^(y3)R^(y4), —N(R^(y3))C(O)R^(y2),—N(R^(y3))S(O)₂R^(y2), —N(R^(y3))C(O)O(R^(y2)),—N(R^(y3))C(O)NR^(y3)R^(y4), —N(R^(y3))S(O)₂NR^(y3)R^(y4), G³, —(C₁-C₆alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(y1), —(C₁-C₆ alkylenyl)-OC(O)R²,—(C₁-C₆ alkylenyl)-OC(O)NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-S(O)₂R¹,—(C₁-C₆ alkylenyl)-S(O)₂NR³R^(y4), —(C₁-C₆ alkylenyl)-C(O)R^(y1),—(C₁-C₆ alkylenyl)-C(O)OR^(y1), —(C₁-C₆ alkylenyl)-C(O)NR³R⁴, —(C₁-C₆alkylenyl)-NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-N(R³)C(O)R^(y2), —(C₁-C₆alkylenyl)-N(R³)S(O)₂R^(y2), —(C₁-C₆ alkylenyl)-N(R³)C(O)O(R^(y2)),—(C₁-C₆ alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-N(R³)S(O)₂NR³R^(y4), —(C₁-C₆ alkylenyl)-CN, or —(C₁-C₆alkylenyl)-G³.

In certain embodiments, R⁷ is H, halogen, —CN, C₁-C₃ alkyl, oroptionally substituted cyclopropyl.

In certain embodiments, R⁷ is H, halogen, C₁-C₃ alkyl, or optionallysubstituted cyclopropyl. In some such embodiments, the cyclopropyl isoptionally substituted with 1, 2, 3, 4, or 5 R^(4g) groups, whereinR^(4g) is C₁-C₃ alkyl, halogen, or C₁-C₃ haloalkyl.

In certain embodiments, R⁷ is H or halogen. In some such embodiments,the halogen is F or C₁. In some such embodiments, the halogen is F.

In certain embodiments, R⁸ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl,—CN, optionally substituted heterocycle, —C(O)NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-NR³R^(y4), —(C₁-C₆ alkylenyl)-N(R³)C(O)R^(y2), —(C₁-C₆alkylenyl)-N(R³)S(O)₂R^(y2), —(C₁-C₆ alkylenyl)-N(R³)C(O)O(R^(y2)),—(C₁-C₆ alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-N(R³)S(O)₂NR³R^(y4), or —(C₁-C₆ alkylenyl)-G³ wherein G³ isoptionally substituted heterocycle.

In certain embodiments, R⁸ is H.

In certain embodiments, R⁹ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl,—CN, —S(O)₂R^(y1), —S(O)₂NR^(y3)R^(y4), —C(O)NR^(y3)R^(y4),—NR^(y3)R^(y4), —N(R^(y3))C(O)R^(y2), —N(R^(y3))S(O)₂R^(y2),—N(R^(y3))C(O)O(R^(y2)), —N(R^(y3))C(O)NR^(y3)R^(y4),—N(R^(y3))S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-CN, —(—(C₁-C₆alkylenyl)-S(O)₂R^(y1), —(C₁-C₆ alkylenyl)-S(O)₂NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-C(O)NR³R^(y4), —(C₁-C₆ alkylenyl)-NR³R^(y4), —(C₁-C₆alkylenyl)-N(R^(y3))C(O)R^(y2), —(C₁-C₆ alkylenyl)-N(R^(y3))S(O)₂R^(y2),—(C₁-C₆ alkylenyl)-N(R³)C(O)O(R^(y2)), —(C₁-C₆alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), or —(C₁-C₆alkylenyl)-N(R³)S(O)₂NR³R^(y4).

In certain embodiments, R⁹ is H, C₁-C₆ alkyl, halogen, —S(O)₂R^(y1),—S(O)₂NR³R^(y4), —NR^(y3)R^(y4), —N(R^(y3))S(O)₂R^(y2), —(C₁-C₆alkylenyl)-CN, or —(C₁-C₆ alkylenyl)-S(O)₂R^(y1).

In certain embodiments, R⁹ is H, C₁-C₆ alkyl, halogen, —S(O)₂R^(y1),—S(O)₂NR^(y3)R^(y4), —NR^(y3)R^(y4), —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆alkylenyl)-S(O)₂R^(y1). In some such embodiments, R^(y1), R^(y3), andR^(y4), at each occurrence, are each independently H or C₁-C₆ alkyl, andR^(y2) is C₁-C₆ alkyl. In some such embodiments, R^(y1) and R^(y2) areC₁-C₃ alkyl, and R^(y3) and R^(y4) are hydrogen.

In certain embodiments, R⁹ is halogen, —NR^(y3)R^(y4),—N(R^(y3))C(O)R^(y2), —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆alkylenyl)-S(O)₂R^(y1).

In certain embodiments, R⁹ is halogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆alkylenyl)-S(O)₂R¹. In some such embodiments, R^(y1) and R^(y2) areC₁-C₆ alkyl, and R^(y3) is H.

In some such embodiments, the halogen is F. In some such embodiments,R^(y1) and R^(y2) are each independently methyl or ethyl, and R^(y3) isH.

In certain embodiments, R⁹ is —(CH₂)—S(O)₂R^(y1). In some suchembodiments, R^(y1) is C₁-C₆ alkyl. In some such embodiments, R^(y1) ismethyl.

In certain embodiments of formula (I), R¹⁰ is H, C₁-C₃ alkyl, halogen,C₁-C₃ haloalkyl, or —CN.

In certain embodiments, R¹⁰ is H, C₁-C₃ alkyl, or halogen.

In certain embodiments, R¹⁰ is H.

Various embodiments of substituents R¹, R², R⁶, Y¹, Y², Y³, A¹, A², A³,and A⁴ have been discussed above. These substituents embodiments can becombined to form various embodiments of compounds of formula (I). Allembodiments of compounds of formula (I), formed by combining thesubstituent embodiments discussed above are within the scope ofApplicant's invention, and some illustrative embodiments of thecompounds of formula (I) are provided below.

In certain embodiments,

-   -   Y¹ is CH;    -   Y³ is CR³; and    -   Y² is CR⁴R⁵.

In certain embodiments,

-   -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵; and    -   R³ is H, —CN, —C(O)R^(3a), —C(O)OR^(3a), —C(O)NR^(3b)R^(3c), or        C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted        with a substituent selected from the group consisting of G¹,        —NR^(3b)R^(3c), N(R^(3b))C(O)R^(3d), N(R^(3b))SO₂R^(3d),        N(R^(3b))C(O)OR^(3d), N(R^(3b))C(O)NR^(3b)R^(3c), and        N(R^(3b))SO₂NR^(3b)R^(3c).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); orA¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   R⁴ is H or deuterium; and    -   R⁵ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₆ haloalkyl, —C(O)R^(5a), —C(O)OR^(5a), or G¹; wherein the        C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each        independently unsubstituted or substituted with 1 or 2        substituents independently selected from the group consisting of        G¹, —C(O)R^(5a), —C(O)OR^(5a), —C(O)NR^(5b)R^(5c),        —C(O)N(R^(5b))NR^(5b)R^(5c), —OR^(5a), —OC(O)R^(5d),        —NR^(5b)R^(5c), N(R^(5b))C(O)R^(5d), N(R^(5b))SO₂R^(5d),        N(R^(5b))C(O)OR^(5d), N(R^(5b))C(O)NR^(5b)R^(5c), and        N(R^(5b))SO₂NR^(5b)R^(5c).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); orA¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵; and    -   R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, —C(O)R^(6a), —C(O)OR^(6a),        —C(O)NR^(6b)R^(6c), —S(O)₂R^(6a), or G²; wherein the C₁-C₆ alkyl        and the C₂-C₆ alkenyl are each independently unsubstituted or        substituted with 1 or 2 substituents independently selected from        the group consisting of G², —CN, —C(O)OR^(6a), —NR^(6b)R^(6c),        N(R^(6b))C(O)R^(6d), N(R^(6b))SO₂R^(6d), N(R^(6b))C(O)OR^(6d),        N(R^(6b))C(O)NR^(6b)R^(6c), and N(R^(6b))SO₂NR^(6b)R^(6c).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); orA¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵; and    -   R⁹ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, —CN, —S(O)₂R¹,        —S(O)₂NR^(y3)R^(y4), —C(O)NR^(y3)R^(y4), —NR^(y3)R^(y4),        —N(R^(y3))C(O)R^(y2), —N(R^(y3))S(O)₂R^(y2),        —N(R^(y3))C(O)O(R^(y2)), —N(R^(y3))C(O)NR^(y3)R^(y4),        —N(R^(y3))S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-S(O)₂R, —(C₁-C₆        alkylenyl)-S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-C(O)NR^(y3)R⁴,        —(C₁-C₆ alkylenyl)-NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-N(R^(y3))C(O)R^(y2), —(C₁-C₆        alkylenyl)-N(R³)S(O)₂R^(y2), —(C₁-C₆        alkylenyl)-N(R³)C(O)O(R^(y2)), —(C₁-C₆        alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), or —(C₁-C₆        alkylenyl)-N(R³)S(O)₂NR^(y3)R^(y4).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); orA¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵; and    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   R¹ is C₁-C₃ alkyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³; and    -   Y² is CR⁴R⁵.

In some further embodiments, R¹ is methyl.

In certain embodiments,

-   -   R¹ is C₁-C₃ alkyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   R⁴ is H or deuterium; and    -   R⁵ is C₂-C₆ alkenyl optionally substituted with a G¹ group, or        R⁵ is H, deuterium, C₁-C₆ alkyl, —C(O)R^(5a), —C(O)OR^(5a), or        G¹; wherein the C₁-C₆ alkyl is unsubstituted or substituted with        a substituent selected from the group consisting of G¹,        —C(O)R^(5a), —C(O)OR^(5a), —C(O)NR^(5b)R^(5c),        —C(O)N(R^(5b))NR^(5b)R^(5c), —OR^(5a), —OC(O)R^(5d),        —NR^(5b)R^(5c), and N(R^(5b))C(NR^(5b)R^(5c))═NR^(5b)R^(5c).

In some further embodiments, R¹ is methyl.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); orA¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   R¹ is C₁-C₃ alkyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵; and    -   R³ is H, —C(O)R^(3a), or —C(O)NR^(3b)R^(3c).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); orA¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In some further embodiments, R¹ is methyl.

In some further embodiments, R¹ is methyl, and R^(3a) is G¹.

In yet some further embodiments, R¹ is methyl, R^(3a) is G¹ wherein G¹is optionally substituted heterocycle.

In certain embodiments,

-   -   R¹ is C₁-C₃ alkyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵; and    -   R⁶ is H, C₁-C₆ alkyl, —C(O)R^(6a), —C(O)OR^(6a),        —C(O)NR^(6b)R^(6c), —S(O)₂R^(6a), or G²; wherein the C₁-C₆ alkyl        is unsubstituted or substituted with a substituent selected from        the group consisting of G² and —C(O)OR^(6a).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); orA¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).

In some further embodiments, R¹ is methyl.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   R¹ is C₁-C₃ alkyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵; and    -   R⁹ is H, C₁-C₆ alkyl, halogen, —S(O)₂R¹, —S(O)₂NR^(y3)R^(y4),        —NR^(y3)R^(y4), —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R¹.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); orA¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In some further embodiments, R¹ is methyl.

In certain embodiments,

-   -   R¹ is C₁-C₃ alkyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵; and    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In yet some further embodiments, R¹ is methyl.

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, —CN, optionally        substituted heterocycle, —C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-NR³R^(y4), —(C₁-C₆ alkylenyl)-N(R^(y3))C(O)R^(y2),        —(C₁-C₆ alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆        alkylenyl)-N(R^(y3))C(O)O(R^(y2)), —(C₁-C₆        alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-N(R^(y3))S(O)₂NR^(y3)R^(y4), or —(C₁-C₆ alkylenyl)-G³        wherein G³ is optionally substituted heterocycle; and    -   R¹⁰ is H, C₁-C₃ alkyl, or halogen.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In one embodiment, the invention is directed to compounds of formula(I), wherein

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, —CN, optionally        substituted heterocycle, —C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-NR³R^(y4), —(C₁-C₆ alkylenyl)-N(R^(y3))C(O)R^(y2),        —(C₁-C₆ alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆        alkylenyl)-N(R³)C(O)O(R^(y2)), —(C₁-C₆        alkylenyl)-N(R³)C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-N(R³)S(O)₂NR^(y3)R^(y4), or —(C₁-C₆ alkylenyl)-G³        wherein G³ is optionally substituted heterocycle;    -   R¹⁰ is H, C₁-C₃ alkyl, or halogen; and    -   R³ is H or —C(O)NR^(3b)R^(3c).

In some further embodiments, R^(3b) and R^(3c) are each independently Hor C₁-C₆ alkyl.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In one embodiment, the invention is directed to compounds of formula(I), wherein

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, —CN, optionally        substituted heterocycle, —C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-NR³R^(y4), —(C₁-C₆ alkylenyl)-N(R^(y3))C(O)R^(y2),        —(C₁-C₆ alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆        alkylenyl)-N(R³)C(O)O(R^(y2)), —(C₁-C₆        alkylenyl)-N(R³)C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-N(R³)S(O)₂NR^(y3)R^(y4), or —(C₁-C₆ alkylenyl)-G³        wherein G³ is optionally substituted heterocycle;    -   R¹⁰ is H, C₁-C₃ alkyl, or halogen; and    -   R⁵ is H, deuterium, or C₁-C₆ alkyl optionally substituted with a        substituent selected from the group consisting of —C(O)OR^(5a)        and OR^(5a).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In yet some further embodiments, R^(5a) is C₁-C₆ alkyl.

In one embodiment, the invention is directed to compounds of formula(I), wherein

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, —CN, optionally        substituted heterocycle, —C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-NR³R^(y4), —(C₁-C₆ alkylenyl)-N(R^(y3))C(O)R^(y2),        —(C₁-C₆ alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆        alkylenyl)-N(R³)C(O)O(R^(y2)), —(C₁-C₆        alkylenyl)-N(R³)C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-N(R³)S(O)₂NR³R^(y4), or —(C₁-C₆ alkylenyl)-G³ wherein        G³ is optionally substituted heterocycle;    -   R¹⁰ is H, C₁-C₃ alkyl, or halogen; and    -   R⁶ is —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c), G², or        C₁-C₆ alkyl which is unsubstituted or substituted with a G²        group.

In some further embodiments, R^(6a) is G² or unsubstituted C₁-C₆ alkyl.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In one embodiment, the invention is directed to compounds of formula(I), wherein

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, —CN, optionally        substituted heterocycle, —C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-NR³R^(y4), —(C₁-C₆ alkylenyl)-N(R^(y3))C(O)R^(y2),        —(C₁-C₆ alkylenyl)-N(R³)S(O)₂R^(y2), —(C₁-C₆        alkylenyl)-N(R³)C(O)O(R^(y2)), —(C₁-C₆        alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-N(R³)S(O)₂NR^(y3)R^(y4), or —(C₁-C₆ alkylenyl)-G³        wherein G³ is optionally substituted heterocycle;    -   R¹⁰ is H, C₁-C₃ alkyl, or halogen; and    -   R⁹ is halogen, —NR^(y3)R^(y4), —N(R^(y3))C(O)R^(y2),        —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆ alkylenyl)-S(O)₂R¹.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰);

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H or halogen;    -   R⁸ is H; and    -   R¹⁰ is H.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰); and    -   R⁴ is H or deuterium;    -   R⁷ is H or halogen;    -   R⁸ is H;    -   R¹⁰ is H; and    -   R⁹ is halogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R^(y1).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In some further embodiments, R^(y1) and R^(y2) are C₁-C₆ alkyl, andR^(y3) is H.

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H or halogen;    -   R⁸ is H;    -   R¹⁰ is H;    -   R⁹ is halogen, —N(R³)S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R^(y1); and    -   R⁶ is —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c), G², or        C₁-C₆ alkyl which is unsubstituted    -   or substituted with a G² group.

In some further embodiments, R^(6a) is G² or unsubstituted C₁-C₆ alkyl.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In some further embodiments, R^(y1) and R^(y2) are C₁-C₆ alkyl, andR^(y3) is H.

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H or halogen;    -   R⁸ is H;    -   R¹⁰ is H;    -   R⁹ is halogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R¹;    -   R⁶ is —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c), G², or        C₁-C₆ alkyl which is unsubstituted    -   or substituted with a G² group; and    -   R⁵ is H, deuterium, or C₁-C₆ alkyl optionally substituted with a        substituent selected from the group consisting of —C(O)OR^(5a)        and OR^(5a).

In some further embodiments, R^(6a) is G² or unsubstituted C₁-C₆ alkyl.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In some further embodiments, R^(y1) and R^(y2) are C₁-C₆ alkyl, andR^(y3) is H.

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H or halogen;    -   R⁸ is H;    -   R¹⁰ is H;    -   R⁹ is halogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R¹;    -   R⁶ is —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c), G², or        C₁-C₆ alkyl which is unsubstituted or substituted with a G²        group;    -   R⁵ is H, deuterium, or C₁-C₆ alkyl optionally substituted with a        substituent selected from the group consisting of —C(O)OR^(5a)        and OR^(5a); and    -   R³ is H or —C(O)NR^(3b)R^(3c).

In some further embodiments, R^(6a) is G² or unsubstituted C₁-C₆ alkyl.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H or halogen;    -   R⁸ is H;    -   R¹⁰ is H;    -   R⁹ is halogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R;    -   R⁶ is —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c), G², or        C₁-C₆ alkyl which is unsubstituted or substituted with a G²        group;    -   R⁵ is H, deuterium, or C₁-C₆ alkyl optionally substituted with a        substituent selected from the group consisting of —C(O)OR^(5a)        and OR^(5a);    -   R³ is H or —C(O)NR^(3b)R^(3c);    -   R^(3b) and R^(3c) are each independently H or C₁-C₆ alkyl;    -   R^(5a) is C₁-C₆ alkyl;    -   R^(y1) and R^(y2) are C₁-C₆ alkyl; and    -   R^(y3) is H.

In some further embodiments, R^(6a) is G² or unsubstituted C₁-C₆ alkyl.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R⁴ is H or deuterium;    -   R⁷ is H or halogen;    -   R⁸ is H;    -   R¹⁰ is H;    -   R⁹ is halogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R¹;    -   R⁶ is G² or C₁-C₆ alkyl which is unsubstituted or substituted        with a G² group;    -   R⁵ is H, deuterium, or C₁-C₆ alkyl optionally substituted with a        substituent selected from the group consisting of —C(O)OR^(5a)        and OR^(5a);    -   R³ is H or —C(O)NR^(3b)R^(3c);    -   R^(3b) and R^(3c) are each independently H or C₁-C₆ alkyl;    -   R^(5a) is C₁-C₆ alkyl;    -   R^(y1) and R^(y2) are C₁-C₆ alkyl; and    -   R^(y3) is H.

In some further embodiments, R⁶ is optionally substituted aryl,optionally substituted heteroaryl, or optionally substituted cycloalkyl;or R⁶ is C₁-C₆ alkyl which is unsubstituted or substituted with asubstituent selected from the group consisting of cycloalkyl andheterocycle, each of which is optionally substituted.

In some further embodiments, R⁶ is optionally substituted phenyl,optionally substituted cyclohexyl, optionally substituted pyridinyl, orC₁-C₆ alkyl which is unsubstituted or substituted with a G² groupwherein G² is cyclopropyl or tetrahydrofuranyl, each of which isoptionally substituted.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In certain embodiments, R¹ is methyl;

-   -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R³ is H, —C(O)NR^(3b)R^(3c), —CN, or C₁-C₆ alkyl which is        substituted with a G¹ group; wherein G¹ is an optionally        substituted C₄-C₆ heterocycle;    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, —CN, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H;    -   R⁹ is halogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R¹; and    -   R¹⁰ is H.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In some further embodiments, R^(3b) is H or C₁-C₆ alkyl; and R^(3c) isH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, G¹, or —(C₁-C₆ alkylenyl)-G¹.

In some further embodiments, R^(3b) and R^(3c) are each independently Hor C₁-C₆ alkyl.

In some further embodiments, R^(y1) and R^(y2) are C₁-C₆ alkyl; andR^(y3) is H.

In certain embodiments, R¹ is methyl;

-   -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R³ is H, —C(O)NR^(3b)R^(3c), —CN, or C₁-C₆ alkyl which is        substituted with a G¹ group;    -   wherein G¹ is an optionally substituted C₄-C₆ heterocycle;    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, —CN, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H;    -   R⁹ is halogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R¹;    -   R¹⁰ is H; and    -   R⁵ is H.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹).

In some further embodiments, A¹ is N, A² is C(R⁵), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁵), A³ is N, and A⁴ isC(R¹⁰).

In some further embodiments, R^(3b) and R^(3c) are each independently Hor C₁-C₆ alkyl.

In some further embodiments, R^(y1) and R^(y2) are C₁-C₆ alkyl; andR^(y3) is H.

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R³ is H, —C(O)NR^(3b)R^(3c), —CN, or C₁-C₆ alkyl which is        substituted with a G¹ group;    -   wherein G¹ is an optionally substituted C₄-C₆ heterocycle;    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, —CN, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H;    -   R⁹ is halogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R¹;    -   R¹⁰ is H;    -   R⁵ is H; and    -   R⁶ is phenyl, pyridinyl, or cyclohexyl; each of which is        optionally substituted; or R⁶ is —C(O)O(C₁-C₆ alkyl); or R⁶ is        —CH₂— (optionally substituted tetrahydropyranyl).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹).

In some further embodiments, R^(3b) and R^(3c) are each independently Hor C₁-C₆ alkyl.

In some further embodiments, R^(y1) and R^(y2) are C₁-C₆ alkyl; andR^(y3) is H.

In certain embodiments, R¹ is methyl;

-   -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R³ is G¹;    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, —CN, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H;    -   R⁹ is —S(O)₂R^(y1), —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R^(y1); and    -   R¹⁰ is H.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In some further embodiments, R^(y1) and R^(y2) are C₁-C₆ alkyl; andR^(y3) is H.

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R³ is G¹; wherein G¹ is optionally substituted heteroaryl;    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, —CN, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H;    -   R⁹ is —S(O)₂RY, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆        alkylenyl)-S(O)₂R^(y1);    -   R¹⁰ is H; and    -   R⁵ is H.

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In some further embodiments, R^(y1) and R^(y2) are C₁-C₆ alkyl; andR^(y3) is H.

In certain embodiments,

-   -   R¹ is methyl;    -   R² is H;    -   Y¹ is CH;    -   Y³ is CR³;    -   Y² is CR⁴R⁵;    -   A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or    -   A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰);    -   R³ is G¹; wherein G¹ is optionally substituted pyrazolyl;    -   R⁴ is H or deuterium;    -   R⁷ is H, halogen, —CN, C₁-C₃ alkyl, or optionally substituted        cyclopropyl;    -   R⁸ is H;    -   R⁹ is —S(O)₂R¹;    -   R¹⁰ is H;    -   R⁵ is H; and    -   R⁶ is phenyl, pyridinyl, or cyclohexyl; each of which is        optionally substituted; or R⁶ is —C(O)O(C₁-C₆ alkyl); or R⁶ is        —CH₂— (optionally substituted tetrahydropyranyl).

In some further embodiments, A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), andA⁴ is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴is C(R¹⁰).

In some further embodiments, A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).

In some further embodiments, R^(y1) is C₁-C₆ alkyl.

In certain embodiments,

-   -   Y¹ is N or CH;    -   R¹ is CD3, C₁-C₃ alkyl, or C₁-C₃ haloalkyl;    -   R² is H or C₁-C₃ alkyl;    -   Y³ is N or CR³;    -   R³ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen,        C₁-C₆ haloalkyl, —C(O)R^(3a), —C(O)OR^(3a), —C(O)NR^(3b)R^(3c),        —S(O)R^(3d), —S(O)₂R^(3a), —S(O)₂NR^(3b)R^(3c), or G¹; wherein        the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each        independently unsubstituted or substituted with 1 or 2        substituents independently selected from the group consisting of        G¹, —C(O)R^(3a), —C(O)OR^(3a), —C(O)NR^(3b)R^(3c),        —C(O)N(R^(3b))NR^(3b)R^(3c), —S(O)R^(3d), —S(O)₂R^(3a),        —S(O)₂NR^(3b)R^(3c), —OR^(3a), —OC(O)R^(3d), —NR^(3b)R^(3c),        N(R^(3b))C(O)R^(3d), N(R^(3b))SO₂R^(3d), N(R^(3b))C(O)OR^(3d),        N(R^(3b))C(O)NR^(3b)R^(3c), N(R^(3b))SO₂NR^(3b)R^(3c), and        N(R^(3b))C(NR^(3b)R^(3c))═NR^(3b)R^(3c);    -   Y² is C(O), S(O)₂, or CR⁴R⁵;    -   R⁴ is H, deuterium, C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl;    -   R⁵ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        halogen, C₁-C₆ haloalkyl, —C(O)R^(5a), —C(O)OR^(5a),        —C(O)NR^(5b)R^(5c), —S(O)R^(5d), —S(O)₂R^(5a),        —S(O)₂NR^(5b)R^(5c), or G¹; wherein the C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted        or substituted with 1 or 2 substituents independently selected        from the group consisting of G¹, —C(O)R^(5a), —C(O)OR^(5a),        —C(O)NR^(5b)R^(5c), —C(O)N(R^(5b))NR^(5b)R^(5c), —S(O)R^(5d),        —S(O)₂R^(5a), —S(O)₂NR^(5b)R^(5c), —OR^(5a), —OC(O)R^(5d),        —NR^(5b)R^(5c), N(R^(5b))C(O)R^(5d), N(R^(5b))SO₂R^(5d),        N(R^(5b))C(O)OR^(5d), N(R^(5b))C(O)NR^(5b)R^(5c),        N(R^(5b))SO₂NR^(5b)R^(5c), and        N(R^(5b))C(NR^(5b)R^(5c))═NR^(5b)R^(5c);    -   R^(3a), R^(3b), R^(3c), R^(5a), R^(5b), and R^(5c), at each        occurrence, are each independently H, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, or —(C₁-C₆        alkylenyl)-G¹;    -   R^(3d) and R^(5d), at each occurrence, are each independently        C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹,        or —(C₁-C₆ alkylenyl)-G¹; G¹, at each occurrence, is        independently aryl, heteroaryl, heterocycle, cycloalkyl, or        cycloalkenyl; and each G¹ is optionally substituted with 1, 2,        3, 4, or 5 R^(1g) groups;    -   R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen,        C₁-C₆ haloalkyl, —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c),        —S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), or G²; wherein the C₁-C₆        alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently        unsubstituted or substituted with 1 or 2 substituents        independently selected from the group consisting of G²,        —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c),        —C(O)N(R^(6b))NR^(6b)R^(6c), —S(O)R^(6d), —S(O)₂R^(6a),        —S(O)₂NR^(6b)R^(6c), —OR^(6a), —OC(O)R^(6d), —NR^(6b)R^(6c),        N(R^(6b))C(O)R^(6d), N(R^(6b))SO₂R^(6d), N(R^(6b))C(O)OR^(6d),        N(R^(6b))C(O)NR^(6b)R^(6c), N(R^(6b))SO₂NR^(6b)R^(6c), and        N(R^(6b))C(NR^(6b)R^(6c))═NR^(6b)R^(6c);    -   R^(6a), R^(6b), and R^(6c), at each occurrence, are each        independently H, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl,        G², —(C₁-C₆ alkylenyl)-G², —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆        alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d),        —(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a),        —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆        alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b),        —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆        alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆        alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆        alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);    -   R^(6d), at each occurrence, is independently alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, haloalkyl, G², —(C₁-C₆ alkylenyl)-G²,        —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a),        —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆        alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆        alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d),        —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆        alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆        alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆        alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆        alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);    -   G², at each occurrence, is independently aryl, heteroaryl,        heterocycle, cycloalkyl, or cycloalkenyl; and each G² is        optionally substituted with 1, 2, 3, 4, or 5 R^(2g) groups;    -   A¹ is C(R⁷) or N; A² is C(R⁸) or N; A³ is C(R⁹) or N; and A⁴ is        C(R¹⁰) or N; wherein zero, one, or two of A¹, A², A³, and A⁴ are        N;    -   R⁷, R⁸, and R⁹, are each independently H, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂,        —OR^(y1), —OC(O)R^(y2), —OC(O)NR^(y3)R^(y4), —SR^(y1), —S(O)₂R,        —S(O)₂NR^(y3)R^(y4), —C(O)R^(y1), —C(O)OR^(y1),        —C(O)NR^(y3)R^(y4), —NR^(y3)R^(y4), —N(R^(y3))C(O)R^(y2),        —N(R^(y3))S(O)₂R^(y2), —N(R^(y3))C(O)O(R^(y2)),        —N(R^(y3))C(O)NR^(y3)R^(y4), —N(R^(y3))S(O)₂NR^(y3)R^(y4), G³,        —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(y1), —(C₁-C₆        alkylenyl)-OC(O)R^(y2), —(C₁-C₆ alkylenyl)-OC(O)NR³R^(y4),        —(C₁-C₆ alkylenyl)-S(O)₂R 1, —(C₁-C₆ alkylenyl)-S(O)₂NR³R^(y4),        —(C₁-C₆ alkylenyl)-C(O)R^(y1), —(C₁-C₆ alkylenyl)-C(O)OR^(y1),        —(C₁-C₆ alkylenyl)-C(O)NR³R⁴, —(C₁-C₆ alkylenyl)-NR³R^(y4),        —(C₁-C₆ alkylenyl)-N(R³)C(O)R^(y2), —(C₁-C₆        alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆        alkylenyl)-N(R³)C(O)O(R^(y2)), —(C₁-C₆        alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), —(C₁-C₆        alkylenyl)-N(R³)S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-CN, or        —(C₁-C₆ alkylenyl)-G³;    -   R^(y1), R^(y3), and R^(y4), at each occurrence, are each        independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₆ haloalkyl, G³, —(C₁-C₆ alkylenyl)-G³, —(C₁-C₆        alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆        alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a),        —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆        alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d),        —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆        alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆        alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆        alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆        alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);    -   R^(y2), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G³, —(C₁-C₆        alkylenyl)-G³, —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆        alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d),        —(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a),        —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆        alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b),        —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆        alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆        alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆        alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);    -   G³, at each occurrence, is independently aryl, heteroaryl,        cycloalkyl, cycloalkenyl, or heterocycle; and each G³ group is        optionally substituted with 1, 2, 3, 4, or 5 R^(4g) groups;    -   R¹⁰ is H, C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, or —CN;    -   R^(1g), R^(2g), and R^(4g), at each occurrence, is independently        selected from the group consisting of oxo, C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂,        G^(2a), —OR, —OC(O)R^(b), —OC(O)NR^(c)R^(d), —SR^(a),        —S(O)₂R^(a), —S(O)₂NR^(c)R^(d), —C(O)R^(a), —C(O)OR^(a),        —C(O)NR^(c)R^(d), —NR^(c)R^(d), —N(R^(e))C(O)R^(b),        —N(R^(e))S(O)₂R^(b), —N(R^(e))C(O)O(R^(b)),        —N(R^(e))C(O)NR^(c)R^(d), —N(R^(e))S(O)₂NR^(c)R^(d), —(C₁-C₆        alkylenyl)-CN, —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆        alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-OC(O)R^(b), —(C₁-C₆        alkylenyl)-OC(O)NR^(C)R^(d), —(C₁-C₆ alkylenyl)-S(O)₂R^(a),        —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆        alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆        alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d),        —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆        alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆        alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆        alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), —(C₁-C₆        alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d), or —(C₁-C₆ alkylenyl)-CN;    -   R^(a), R^(c), R^(d), and R^(e), at each occurrence, are each        independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₆ haloalkyl, G^(2a), or —(C₁-C₆ alkylenyl)-G^(2a);    -   R^(b), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2a), or —(C₁-C₆        alkylenyl)-G^(2a);    -   G^(2a), at each occurrence, are each independently aryl,        heteroaryl, heterocycle, cycloalkyl, or cycloalkenyl; and each        G^(2a) group is optionally substituted with 1, 2, 3, 4, or 5        R^(3g) groups;    -   R^(3g), at each occurrence, is independently oxo, C₁-C₆ alkyl,        C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN,        NO₂, —OR^(z1), —OC(O)R^(z2), —OC(O)NR^(z3)R^(z4), —SR^(z1),        —S(O)₂R^(z1), —S(O)₂NR^(z3)R^(z4), —C(O)R^(z1), —C(O)OR^(z1),        —C(O)NR^(z3)R^(z4), —NR^(z3)R^(z4), —N(R^(z3))C(O)R^(z2),        —N(R^(z3))S(O)₂R^(z2), —N(R^(z3))C(O)O(R^(z2)),        —N(R^(z3))C(O)NR^(z3)R^(z4), —N(R^(z3))S(O)₂NR^(z3)R^(z4),        —(C₁-C₆ alkylenyl)-OR^(z1), —(C₁-C₆ alkylenyl)-OC(O)R^(z2),        —(C₁-C₆ alkylenyl)-OC(O)NR^(z3)R^(z4), —(C₁-C₆        alkylenyl)-S(O)₂R^(z1), —(C₁-C₆ alkylenyl)-S(O)₂NR^(z3)R^(z4),        —(C₁-C₆ alkylenyl)-C(O)R^(z1), —(C₁-C₆ alkylenyl)-C(O)OR^(z1),        —(C₁-C₆ alkylenyl)-C(O)NR^(z3)R^(z4), —(C₁-C₆        alkylenyl)-NR^(z3)R^(z4), —(C₁-C₆        alkylenyl)-N(R^(z3))C(O)R^(z2), —(C₁-C₆        alkylenyl)-N(R^(z3))S(O)₂R^(z2), —(C₁-C₆        alkylenyl)-N(R^(z3))C(O)O(R^(z2)), —(C₁-C₆        alkylenyl)-N(R^(z3))C(O)NR³R⁴, —(C₁-C₆        alkylenyl)-N(R^(z3))S(O)₂NR^(z3)R^(z4), or —(C₁-C₆        alkylenyl)-CN;    -   R^(z1), R^(z3), and R^(z4), at each occurrence, are each        independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or        C₁-C₆ haloalkyl; and    -   R^(z2), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl.

In certain embodiments,

-   Y is N or CH;-   R¹ is CD3, C₁-C₃ alkyl, or C₁-C₃ haloalkyl;-   R² is H or C₁-C₃ alkyl;-   Y³ is N or CR³;-   R³ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆    haloalkyl, —CN, —C(O)R^(3a), —C(O)OR^(3a), —C(O)NR^(3b)R^(3c),    —S(O)R^(3d), —S(O)₂R^(3a), —S(O)₂NR^(3b)R^(3c), or G¹; wherein the    C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently    unsubstituted or substituted with 1 or 2 substituents independently    selected from the group consisting of G¹, —CN, —C(O)R^(3a),    —C(O)OR^(3a), —C(O)NR^(3b)R^(3c), —C(O)N(R^(3b))NR^(3b)R^(3c),    —S(O)R^(3d), —S(O)₂R^(3a), —S(O)₂NR^(3b)R^(3c), —OR^(3a),    —OC(O)R^(3d), —NR^(3b)R^(3c), N(R^(3b))C(O)R^(3d),    N(R^(3b))SO₂R^(3d), N(R^(3b))C(O)OR^(3d),    N(R^(3b))C(O)NR^(3b)R^(3c), N(R^(3b))SO₂NR^(3b)R^(3c), and    N(R^(3b))C(NR^(3b)R^(3c))═NR^(3b)R^(3c);-   Y² is C(O), S(O)₂, or CR⁴R⁵;-   R⁴ is H, deuterium, C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl;-   R⁵ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    halogen, C₁-C₆ haloalkyl, —C(O)R^(5a), —C(O)OR^(5a),    —C(O)NR^(5b)R^(5c), —S(O)R^(5d), —S(O)₂R^(5a), —S(O)₂NR^(5b)R^(5c),    or G¹; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are    each independently unsubstituted or substituted with 1 or 2    substituents independently selected from the group consisting of G¹,    —C(O)R^(5a), —C(O)OR^(5a), —C(O)NR^(5b)R^(5c),    —C(O)N(R^(5b))NR^(5b)R^(5c), —S(O)R^(5d), —S(O)₂R^(5a),    —S(O)₂NR^(5b)R^(5c), —OR^(5a), —OC(O)R^(5d), —NR^(5b)R^(5c),    N(R^(5b))C(O)R^(5d), N(R^(5b))SO₂R^(5d), N(R^(5b))C(O)OR^(5d),    N(R^(5b))C(O)NR^(5b)R^(5c), N(R^(5b))SO₂NR^(5b)R^(5c), and    N(R^(5b))C(NR^(5b)R⁵)═NR^(5b)R^(5c);-   R^(3a), R^(3b), R^(3c), R^(5a), and R^(5b), at each occurrence, are    each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    C₁-C₆ haloalkyl, G¹, or —(C₁-C₆ alkylenyl)-G¹;-   R^(5c), at each occurrence, is independently H, C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, —(C₁-C₆ alkylenyl)-G¹,    —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(a), or —(C₁-C₆    alkylenyl)-C(O)OR^(a);-   R^(3d), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, or —(C₁-C₆    alkylenyl)-G¹;-   R^(5d), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, —(C₁-C₆ alkylenyl)-G¹,    —(C₁-C₆ alkylenyl)-NR^(c)R^(d), or —(C₁-C₆    alkylenyl)-N(R^(e))C(O)O(R^(b));-   G¹, at each occurrence, is independently aryl, heteroaryl,    heterocycle, cycloalkyl, or cycloalkenyl; and each G¹ is optionally    substituted with 1, 2, 3, 4, or 5 R^(1g) groups;-   R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆    haloalkyl, —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c),    —S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), or G²; wherein the C₁-C₆ alkyl,    C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently    unsubstituted or substituted with 1 or 2 substituents independently    selected from the group consisting of G², —C(O)R^(6a), —C(O)OR^(6a),    —C(O)NR^(6b)R^(6c), —C(O)N(R^(6b))NR^(6b)R^(6c), —S(O)R^(6d),    —S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), —OR^(6a), —OC(O)R^(6d),    —NR^(6b)R^(6c), N(R^(6b))C(O)R^(6d), N(R^(6b))SO₂R^(6d),    N(R^(6b))C(O)OR^(6d), N(R^(6b))C(O)NR^(6b)R^(6c),    N(R^(6b))SO₂NR^(6b)R^(6c), and    N(R^(6b))C(NR^(6b)R^(6c))═NR^(6b)R^(6c);-   R^(6a), R^(6b), and R^(6c), at each occurrence, are each    independently H, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G²,    —(C₁-C₆ alkylenyl)-G², —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆    alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆    alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆    alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),    —(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆    alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);-   R^(6d), at each occurrence, is independently alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, haloalkyl, G², —(C₁-C₆ alkylenyl)-G², —(C₁-C₆    alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆    alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆    alkylenyl)-C(O)OR^(a), —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆    alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b),    —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆    alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);-   G², at each occurrence, is independently aryl, heteroaryl,    heterocycle, cycloalkyl, or cycloalkenyl; and each G² is optionally    substituted with 1, 2, 3, 4, or 5 R^(2g) groups;-   A¹ is C(R⁷) or N; A² is C(R⁸) or N; A³ is C(R⁹) or N; and A⁴ is    C(R¹⁰) or N; wherein zero, one, or two of A¹, A², A³, and A⁴ are N;-   R⁷, R⁸, and R⁹, are each independently H, C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂,    —OR^(y1), —OC(O)R^(y2), —OC(O)NR^(y3)R^(y4), —SR^(y1), —S(O)₂R^(y1),    —S(O)₂NR³R^(y4), —C(O)R^(y1), —C(O)OR^(y1), —C(O)NR^(y3)R^(y4),    —NR^(y3)R^(y4), —N(R^(y3))C(O)R^(y2), —N(R^(y3))S(O)₂R^(y2),    —N(R^(y3))C(O)O(R^(y2)), —N(R^(y3))C(O)NR^(y3)R^(y4),    —N(R^(y3))S(O)₂NR^(y3)R^(y4), G³, —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆    alkylenyl)-OR^(y1), —(C₁-C₆ alkylenyl)-OC(O)R^(y2), —(C₁-C₆    alkylenyl)-OC(O)NR³R^(y4), —(C₁-C₆ alkylenyl)-S(O)₂R¹, —(C₁-C₆    alkylenyl)-S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-C(O)R^(y1),    —(C₁-C₆ alkylenyl)-C(O)OR^(y1), —(C₁-C₆ alkylenyl)-C(O)NR³R⁴,    —(C₁-C₆ alkylenyl)-NR³R^(y4), —(C₁-C₆    alkylenyl)-N(R^(y3))C(O)R^(y2), —(C₁-C₆    alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆    alkylenyl)-N(R³)C(O)O(R^(y2)), —(C₁-C₆    alkylenyl)-N(R³)C(O)NR^(y3)R^(y4), —(C₁-C₆    alkylenyl)-N(R³)S(O)₂NR³R⁴, —(C₁-C₆ alkylenyl)-CN, or —(C₁-C₆    alkylenyl)-G³;-   R^(y1), R^(y3), and R^(y4), at each occurrence, are each    independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆    haloalkyl, G³, —(C₁-C₆ alkylenyl)-G³, —(C₁-C₆ alkylenyl)-OR^(a),    —(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d),    —(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆    alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),    —(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆    alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);-   R^(y2), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G³, —(C₁-C₆ alkylenyl)-G³,    —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆    alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁—C₆    alkylenyl)-C(O)OR^(a), —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆    alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b),    —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆    alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d);-   G³, at each occurrence, is independently aryl, heteroaryl,    cycloalkyl, cycloalkenyl, or heterocycle; and each G³ group is    optionally substituted with 1, 2, 3, 4, or 5 R^(4g) groups;-   R¹⁰ is H, C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl, or —CN;-   R^(1g), R^(2g), and R^(4g), at each occurrence, is independently    selected from the group consisting of oxo, C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, G^(2a),    —OR^(a), —OC(O)R^(b), —OC(O)NR^(c)R^(d), —SR^(a), —S(O)₂R^(a),    —S(O)₂NR^(c)R^(d), —C(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(d),    —NR^(c)R^(d), —N(R^(e))C(O)R^(b), —N(R^(e))S(O)₂R^(b),    —N(R^(e))C(O)O(R^(b)), —N(R^(e))C(O)NR^(c)R^(d),    —N(R^(e))S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆    alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆    alkylenyl)-OC(O)R^(b), —(C₁-C₆ alkylenyl)-OC(O)NR^(c)R^(d), —(C₁-C₆    alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆    alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆    alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),    —(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆    alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), —(C₁-C₆    alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d), or —(C₁-C₆ alkylenyl)-CN;-   R^(a), R^(c), R^(d), and R^(e), at each occurrence, are each    independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆    haloalkyl, G^(2a), or —(C₁-C₆ alkylenyl)-G^(2a);-   R^(b), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2a), or —(C₁-C₆    alkylenyl)-G^(2a);-   G^(2a), at each occurrence, are each independently aryl, heteroaryl,    heterocycle, cycloalkyl, or cycloalkenyl; and each G^(2a) group is    optionally substituted with 1, 2, 3, 4, or 5 R^(3g) groups;-   R^(3g), at each occurrence, is independently oxo, C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂,    —OR^(z1), —OC(O)R^(z2), —OC(O)NR^(z3)R^(z4), —SR^(z1), —S(O)₂R^(z1),    —S(O)₂NR^(z3)R^(z4), —C(O)R^(z1), —C(O)OR^(z1), —C(O)NR^(z3)R^(z4),    —NR^(z3)R^(z4), —N(R^(z3))C(O)R^(z2), —N(R^(z3))S(O)₂R^(z2),    —N(R^(z3))C(O)O(R^(z2)), —N(R^(z3))C(O)NR^(z3)R^(z4),    —N(R^(z3))S(O)₂NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-OR^(z1), —(C₁-C₆    alkylenyl)-OC(O)R^(z2), —(C₁-C₆ alkylenyl)-OC(O)NR^(z3)R^(z4),    —(C₁-C₆ alkylenyl)-S(O)₂R^(z1), —(C₁-C₆    alkylenyl)-S(O)₂NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-C(O)R^(z1),    —(C₁-C₆ alkylenyl)-C(O)OR^(z1), —(C₁-C₆    alkylenyl)-C(O)NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-NR^(z3)R^(z4),    —(C₁-C₆ alkylenyl)-N(R^(z3))C(O)R^(z2), —(C₁-C₆    alkylenyl)-N(R^(z3))S(O)₂R^(z2), —(C₁-C₆    alkylenyl)-N(R^(z3))C(O)O(R^(z2)), —(C₁-C₆    alkylenyl)-N(R^(z3))C(O)NR³R⁴, —(C₁-C₆    alkylenyl)-N(R^(z3))S(O)₂NR^(z3)R^(z4), or —(C₁-C₆ alkylenyl)-CN;-   R^(z1), R^(z3), and R^(z4), at each occurrence, are each    independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆    haloalkyl; and-   R^(z2), at each occurrence, is independently C₁-C₆ alkyl, C₂-C₆    alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl.

Compounds of formula (I) may contain one or more asymmetricallysubstituted atoms. Compounds of formula (I) may also exist as individualstereoisomers (including enantiomers and diastereomers) and mixturesthereof. Individual stereoisomers of compounds of formula (I) may beprepared synthetically from commercially available starting materialsthat contain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution of the individual stereoisomer usingmethods that are known to those of ordinary skill in the art. Examplesof resolution are, for example, (i) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography, followed byliberation of the optically pure product; or (ii) separation of themixture of enantiomers or diastereomers on chiral chromatographiccolumns.

Compounds of formula (I) may also include the various geometric isomersand mixtures thereof resulting from the disposition of substituentsaround a carbon-carbon double bond, a carbon-nitrogen double bond, acycloalkyl group, or a heterocycle group. Substituents around acarbon-carbon double bond or a carbon-nitrogen double bond aredesignated as being of Z or E configuration and substituents around acycloalkyl or heterocycle are designated as being of cis or transconfiguration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism and alltautomeric isomers are included in the scope of the invention.

Thus, the formula drawings within this specification can represent onlyone of the possible tautomeric, geometric, or stereoisomeric forms. Itis to be understood that the invention encompasses any tautomeric,geometric, or stereoisomeric form, and mixtures thereof, and is not tobe limited merely to any one tautomeric, geometric, or stereoisomericform utilized within the formula drawings.

Compounds of the invention are named using ChemDraw Ultra Version 12.0.

Exemplary compounds of formula (I) include, but are not limited to:

-   4-(cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(cyclopropylmethyl)-3-ethyl-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;    ethyl    4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;-   4-(4-fluorophenyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-7-sulfonamide;-   4-(4-fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   methyl    3-(4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;-   4-(cyclopropylmethyl)-3-(2-methoxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   3-benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   methyl    3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;-   10-methyl-7-((methylsulfonyl)methyl)-3-phenethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   3-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   (E)-3-(4-fluorostyryl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   7-amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;-   N-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide;-   N-(4-(2,4-difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide;-   4-butyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   tert-butyl    3-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)pyrrolidine-1-carboxylate;-   10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-((4,4-difluorocyclohexyl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   tert-butyl    4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)piperidine-1-carboxylate;-   10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydro-2H-pyran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4,4-difluorocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-fluorophenyl)-(3,3-²H₂)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   7-fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-fluorophenyl)-7,10-dimethyl-3-phenyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;-   ethyl    4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;-   tert-butyl    4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carbonyl)piperazine-1-carboxylate;-   10-methyl-7-((methylsulfonyl)methyl)-4-(pyrrolidin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(piperidin-4-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   7-fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;-   ethyl    7-fluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-3-carboxylate;-   4-(4-fluorophenyl)-3-(4-methoxypiperidine-1-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-fluorophenyl)-10-methyl-3-(4-methylpiperazine-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   5,7-difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   ethyl    4-(4-fluorophenyl)-7,10-dimethyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-3-carboxylate;-   N-cyclopentyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   4-butyl-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   5,7-difluoro-10-methyl-4-propyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(cyclopropylmethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   methyl    4-(5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)butanoate;-   5,7-difluoro-10-methyl-4-(3-phenylpropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(o-tolyl)-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   2-ethylhexyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   4-isobutyryl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   5,7-difluoro-10-methyl-4-phenethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-((1Z,3E)-2,4-diphenylbuta-1,3-dien-1-yl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;-   4-(4-chlorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;-   4-(4-chlorophenyl)-10-methyl-2-(4-methylpiperazine-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   N-(2,6-dimethylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-(4-methoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-(4-ethylphenethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-propyl-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-(3-methoxybenzyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-(2-chloroethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-(cyclohexylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-(4-isopropylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-(2,6-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   ethyl    4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4-carboxamido)methyl)cyclohexanecarboxylate;-   N-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;-   10-methyl-7-((methylsulfonyl)methyl)-4-tosyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-([1,1′-biphenyl]-4-ylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-((4-methoxyphenyl)sulfonyl)-10-mmethylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(phenylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-((2-methoxyphenyl)sulfonyl)-10-mmethylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-((4-phenoxyphenyl)sulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-((4-fluorophenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   methyl    3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;-   4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentaazadibenzo[cd,f]azulen-11(10H)-one;-   (R)-ethyl    4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;-   (S)-ethyl    4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;-   2-methoxyethyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   ethyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   pentyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   4-chlorobutyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   naphthalen-2-yl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   p-tolyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   neopentyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   phenyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   4-fluorophenyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   2-methoxyphenyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   2-fluoroethyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   4-methoxyphenyl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   but-2-yn-1-yl    10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide;-   4-(4-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(3-methoxypropanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-([1,1′-biphenyl]-4-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(3-cyclopentylpropanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2-(3-methoxyphenyl)acetyl)-10-mmethylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-propionyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-4-(3-methylbutanoyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(3,3-dimethylbutanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(2-phenylacetyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-benzoyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-methoxybenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   methyl    4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)-4-oxobutanoate;-   4-(2,4-difluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(1-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(cyclopropanecarbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(3-phenylpropanoyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione;-   3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-methylpropanamide;-   3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N,N-dimethylpropanamide;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-morpholino-3-oxopropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(tetrahydro-2H-pyran-4-yl)propanamide;-   3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N′-methyl-N′-phenylpropanehydrazide;-   N-benzyl-3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide;-   3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)propanamide;-   tert-butyl    4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoyl)piperazine-1-carboxylate;-   tert-butyl    4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamido)piperidine-1-carboxylate;-   4-(4-chlorophenyl)-N-ethyl-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;-   6-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)hexyl    acetate;-   3-(aminomethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   N-((((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)(dimethylamino)methylene)-N-methylmethanaminium;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-oxo-3-(piperazin-1-yl)propyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(piperidin-4-yl)propanamide;-   4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)butane-1,2-diyl    diacetate;-   methyl    5-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)pentanoate;-   tert-butyl    (2-(((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)-2-oxoethyl)carbamate;-   4-(2,4-difluorophenyl)-3-(6-hydroxyhexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)benzamide;-   1-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)-3-phenylurea;-   2-amino-N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)acetamide;-   4-(2,4-difluorophenyl)-3-(3,4-dihydroxybutyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   4-(2,4-difluorophenyl)-3-(3-hydroxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   (S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   (R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-3-(3-ethoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-((1-ethylpiperidin-3-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-ethoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   N-(2-cyanoethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   methyl    2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamido)acetate;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-phenethyl-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   N-butyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   N-cyclohexyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   N-benzyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(3-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   4-(2,4-difluorophenyl)-N-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   4-(2,4-difluorophenyl)-N-(2-hydroxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-N-(oxazol-4-ylmethyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   N-(cyclopropylmethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   4-(2,4-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   4-(2,4-difluorophenyl)-N-(1-(hydroxymethyl)cyclopropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   4-(2,4-difluorophenyl)-10-methyl-N-(1-methylcyclopropyl)-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(4-phenylbutyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;-   4-(3,3-dimethylbutanoyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   tert-butyl    ((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;-   4-((trans)-4-aminocyclohexyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(cyclopropylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   ethyl    5,7-difluoro-10-methyl-1-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;-   4-(2,4-difluorophenyl)-10-methyl-3-(3-(methylamino)propyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-3-(3-(dimethylamino)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   2-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-7-yl)acetonitrile;-   4-(2,2-dimethyl-3-(pyrrolidin-1-yl)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   2-(3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)pyrrolidin-1-yl)acetic    acid;-   10-methyl-7-((methylsulfonyl)methyl)-4-(2-methyltetrahydrofuran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-4-(1-methylpiperidin-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-((1-isopropylpiperidin-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(1-(2-oxotetrahydrofuran-3-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(1-methoxypropan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-methoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-4-(1-methylpyrrolidin-3-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-4-(1-methylazepan-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(1-ethylpiperidin-3-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)benzonitrile;-   4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinomethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   N-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;-   5-cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   tert-butyl    (4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;-   tert-butyl    ((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;-   4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;-   4-(2,4-difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;-   4-(2,4-difluorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;-   4-(4-cyanophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;-   (S)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione;-   (R)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrile;-   10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   ethyl    4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;-   10-methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-aminocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(3,5-difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   (R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   (S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(naphthalen-1-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-(3,3-²H₂)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-neopentyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((1-oxoisoindolin-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-3-(2,6-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-3-(3,5-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   3-(3,5-di-tert-butylphenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   methyl    (4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;-   methyl    ((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;-   methyl    ((cis)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;-   2-(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)isoindoline-1,3-dione;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-1(10H)-one;-   benzyl    (2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)carbamate;-   3-([1,1′-biphenyl]-2-yl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(quinolin-8-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   3-(4-(1H-imidazol-1-yl)phenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-(pyridin-2-yl)phenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-1(10H)-one;-   3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   ethyl    4-(2,4-difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;-   4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide;-   4-(2,4-difluorophenyl)-N,    10-dimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide;-   4-(2,4-difluorophenyl)-N,N,    10-trimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide;-   N-(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)acetamide;-   10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(5-chloropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(1H-indazol-5-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(pyridazin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   (S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   (R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2-fluoropyridin-4-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(6-methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2,2-dimethyl-3-morpholinopropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(5-fluoropyrimidin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   2-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)-2-phenylacetonitrile;-   2-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)phenoxy)acetamide;    4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylic    acid;-   10-methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)benzyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   (R)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-4-(pyridin-2-yl)-7-(pyrrolidin-1-ylsulfonyl)-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;-   (S)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   (R)-methyl    3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;-   (S)-methyl    3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;-   4-(2,4-difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   4-(4-chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   (R)—N-ethyl-7-(ethylsulfonyl)-10-methyl-11-oxo-4-(1-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;-   10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-1    (10H)-one;-   10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;-   10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;    and    4-(4-fluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;    or pharmaceutically acceptable salts thereof.

Compounds of formula I can be used in the form of pharmaceuticallyacceptable salts. The phrase “pharmaceutically acceptable salt” meansthose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts have been described in S. M. Berge etal. J. Pharmaceutical Sciences, 1977, 66: 1-19.

Compounds of formula (I) may contain either a basic or an acidicfunctionality, or both, and can be converted to a pharmaceuticallyacceptable salt, when desired, by using a suitable acid or base. Thesalts may be prepared in situ during the final isolation andpurification of the compounds of the invention.

Examples of acid addition salts include, but are not limited to acetate,adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isothionate), lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequatemized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which maybe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts may be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Other examples oforganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, piperazineand the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The present invention contemplates compounds of formula (I) formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

Compounds described herein can exist in unsolvated as well as solvatedforms, including hydrated forms, such as hemi-hydrates. In general, thesolvated forms, with pharmaceutically acceptable solvents such as waterand ethanol among others are equivalent to the unsolvated forms for thepurposes of the invention.

General Synthesis

The compounds described herein, including compounds of general formula(I) and specific examples, may be prepared, for example, through thereaction routes depicted in schemes 1-6. The variables A¹, A², A³, A⁴,Y¹, Y², Y³, R¹, R², R³, R⁴, R⁵, R⁶, R^(3b), R^(3c), R^(6a), R^(6b), andR^(6c) used in the following schemes have the meanings as set forth inthe summary and detailed description sections unless otherwise noted.

Abbreviations used in the descriptions of the schemes and the specificexamples have the following meanings: DMF for dimethylformamide, DMSOfor dimethyl sulfoxide, mCPBA for 3-chloroperbenzoic acid, Pd(OAc)₂ forpalladium(II) acetate, SFC for Supercritical Fluid Chromatography, THFfor tetrahydrofuran, TFA for trifluoroacetic acid, and HPLC for highperformance liquid chromatography.

Compounds of general formula (I) wherein Y² is CR⁴R⁵ may be prepared bytreating compounds of general formula (1) with an aldehyde or ketone (2)under acidic conditions, as illustrated in Scheme 1. Generally thiscyclization reaction may be effected in the presence of a reagent suchas titanium tetrachloride in a solvent such as, but not limited to,tetrahydrofuran or dichloromethane, at a temperature ranging from 0° C.to 50° C. Alternatively, this cyclization reaction may also be effectedin the presence of an acid, such as acetic acid or hydrochloric acid, inthe absence or presence of a solvent such as, but not limited to,methanol or ethanol, at a temperature ranging from 50° C. to 150° C.

Compounds of formula (1) wherein Y¹ and Y³ are CH and R² is H may beprepared by general synthetic methods as shown in Scheme 2. Treatment ofcompounds of formula (4) wherein X is Br, Cl, or I, with1,1-dimethoxy-N,N-dimethylmethanamine at elevated temperature (e.g.about 60° C. to about 100° C.), in the absence or presence of a base,and in a solvent such as, but not limited to, DMF, provide compounds offormula (5). Examples of suitable bases include, but are not limited to,lithium or sodium methanolate. Catalytic hydrogenation of (5) in thepresence of a catalyst such as, but not limited to, Raney-Nickel andunder hydrogen atmosphere (about 30 psi) and in a solvent such as, butnot limited to, ethyl acetate, at about room temperature generallyaffords compounds of formula (6). Protection of the nitrogen atom withprotecting group such as, but not limited to, benzyl, tosyl, or(trimethylsilyl)ethoxy)methyl group may be derived from reaction with anappropriate halide in the presence of a strong base such as, but notlimited to, sodium hydride, to provide compounds of formula (7).

Treatment of (7) with an acid such as, but not limited to, hydrochloricacid or hydrobromic acid and in a solvent such as, but not limited to,dioxane or water, at about 40° C. to about 100° C., typically providescompounds of formula (8).

Alkylation of (8) with an halide or mesylate, in the presence of a basesuch as, but not limited to, sodium hydride, cesium carbonate, orpotassium carbonate, and in a solvent such as, but not limited to,dimethylformamide or dimethylsulfoxide at a temperature of about 0° C.to about 50° C. provides compounds of formula (9).

Treatment of the compounds of formula (9) with4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) affordscompounds of formula (10). In general, the conversion may be facilitatedby a palladium catalyst such as, but not limited to,tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), or palladium(II)acetate, anoptional ligand such as, but not limited to,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), or1,1′-bis(diphenylphosphanyl) ferrocene, and a base such as, but notlimited to, carbonates, acetates, or phosphates.of sodium, potassium,and cesium; and cesium fluoride. Non-limiting examples of suitablesolvents include methanol, dimethoxyethane, N,N-dimethylformamide,dimethylsulfoxide, dioxane, tetrahydrofuran, and water, or a mixturethereof. Compounds of formula (13) may be prepared by (a) treatingcompounds of formula (10) with compounds of formula (11) wherein X¹⁰¹ ishalide, mesylate, or triflate, under Suzuki coupling conditions (N.Miyama and A. Suzuki, Chem. Rev. 1995, 95:2457-2483, J. Organomet. Chem.1999, 576:147-148), to provide compounds of formula (12), and (b)removal of the protecting group (PG), as illustrated in Scheme 2.Removal of the protecting group may also occur in situ under the Suzukireaction conditions. Generally, the coupling reaction is effected in thepresence of a palladium catalyst and a base, and optionally in thepresence of a ligand, and in a suitable solvent at elevated temperature(for example, at about 80° C. to about 150° C.). The reaction may befacilitated by microwave irradiation. Examples of the palladium catalystinclude, but are not limited to,tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0), and palladium(II)acetate.Examples of suitable bases that may be employed include, but not limitedto, carbonates or phosphates of sodium, potassium, and cesium; andcesium fluoride. Examples of suitable ligands include, but not limitedto, 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), and1,1′-bis(diphenylphosphanyl) ferrocene. Non-limiting examples ofsuitable solvent include methanol, dimethoxyethane,N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, andwater, or a mixture thereof.

Alternatively, treatment of compounds of formula (9) wherein X is I, Br,Cl, or triflate with boronic acid or derivatives thereof (e.g. boronicesters) of formula (14), under Suzuki coupling conditions as describedabove, may also afford compounds of formula (12). Removal of theprotecting group may take place under the Suzuki reaction conditions toprovide compounds of formula (13).

Compounds of formula (11) wherein X¹⁰¹ is I, Br, or Cl and formula (14)may be prepared according to the synthesis outlined in Scheme 3.Reductive amination of amines (15) wherein X¹⁰¹ is I, Br, or Cl with asuitable aldehyde or ketone in the presence of a reducing agent such as,for example, sodium triacetoxyhydroborate, sodium borohydride, or sodiumcyanoborohydride, and an acid (e.g. acetic acid), provides compounds(11) wherein R⁶ is C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, each ofwhich is optionally substituted, or R⁶ is C₁-C₆ haloalkyl. The reactionis generally conducted in a solvent such as, for example,dichloromethane, methanol, or ethanol, at a temperature of about 0° C.to about 100° C. Compounds of formula (14) may be prepared fromcompounds of formula (11) under Suzuki coupling conditions as describedin Scheme 2.

Alternatively, compounds of formula (11) may be prepared using Buchwaldreaction conditions. Halides (16) may be treated with a suitable amine(17) in the presence of a catalyst, a ligand, a base, and in a solventto provide compounds of formula (18). Examples of catalysts that may beemployed include, but are not limited to,tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),bis(triphenylphosphine)palladium(II) dichloride, andpalladium(II)acetate. Examples of suitable bases that may be employedinclude, but not limited to, carbonates or phosphates of sodium,potassium, and cesium, and cesium fluoride. Examples of suitable ligandsinclude, but are not limited to,1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), and1,1′-bis(diphenylphosphanyl) ferrocene. Non-limiting examples ofsuitable solvent include toluene, tert-butanol, methanol, ethanol,dimethoxyethane, N,N-dimethylformamide, dimethylsulfoxide, dioxane,tetrahydrofuran, and water, or a mixture thereof. Halogenation ofcompounds of formula (18) by reaction with a reagent such as, but notlimited to, N-bromosuccinimide or N-iodosuccinimide, in a solvent suchas, but not limited to, acetic acid, at temperatures from about 0° C. toabout 50° C., provides compounds of formula (11) wherein X¹⁰¹ is I orBr.

Compounds of general formula (3) wherein R² is H may be preparedaccording to the synthesis outlined in Scheme 4. Compounds of formula(20) may be prepared by treating compounds of formula (18) with (15)wherein X¹⁰¹ is halide, mesylate, or triflate under Suzuki couplingconditions as described in Scheme 2. Compounds of formula (20) may alsobe prepared by treating compounds of formula (21), wherein X¹⁰³ ishalide, mesylate, or triflate, with a boronic acid (or a boronic acidderivative) (22) under Suzuki coupling conditions. Deprotection ofcompound (20) under suitable conditions provides compounds of formula(23). Compounds of formula (24) may be prepared by treating compounds ofthe formula (23) with an aldehyde or ketone (2) using conditionsdescribed in Scheme 1. Compounds of formula (25) wherein R⁶ isoptionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, orR⁶ is C₁-C₆ haloalkyl may be prepared by the reductive aminationreaction of compounds of formula (24) with suitable aldehydes orketones, employing reaction conditions described in Scheme 3. Similarly,reductive amination of compounds of formula (20) with suitable aldehydesor ketones provides compounds of formula (26). Compounds of generalformula (25) wherein R⁶ is C(O)OR^(6a), C(O)R^(6a), S(O)₂R^(6a), andC(O)NR^(6b)R^(6c) may be prepared by the reaction of compounds offormula (24) with chloroformates, acid chlorides, sulfonyl chlorides orisocyanates in the presence of a base such as, but not limited to,diisopropylethylamine, triethylamine, or cesium carbonate, in a solventsuch as dimethylformamide, dimethylacetamide, 1,2-dichloroethane, ordichloromethane, at temperatures ranging from ambient temperature toabout 100° C. for about 2 to about 72 hours.

Compounds of formula (21) wherein X¹⁰³ is Cl, Y¹ is N and Y³ is CH maybe prepared according to the synthesis described in Scheme 5. Treatmentof (27) with ammonium hydroxide at about 100° C. to about 150° C.affords amines of formula (28).

Iodination of (28) with N-iodosuccinimide in a solvent such as, but notlimited to, acetonitrile or acetone, at a temperature of about 40° C. toabout 85° C., yields compounds of formula (29). Subsequent coupling with(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane utilizingSuzuki coupling reaction conditions as described above providescompounds of formula (30). Cyclization of (30) followed by protection ofthe nitrogen atom affords compounds of formula (31).

Cyclization of (30) may be accomplished in the presence of an acid suchas, but not limited to, acetic acid or hydrochloric acid and at anelevated temperature (e.g. about 50° C. to about 100° C.).

Compounds of formula (38) may be prepared according to Scheme 6. Estersof formula (33) may be obtained from (a) treatment of formula (4) withdiethyl oxalate in the presence of a base such as, but not limited to,potassium ethoxide or sodium ethoxide, in a solvent such as, but notlimited to, ethanol, dioxane, and diethyl ether, and at a temperature ofabout 40° C. to about 80° C.; and (b) cyclization of the resultingintermediate (32) in the presence of iron and in ethanol and aceticacid, at a temperature of about 80° C. to about 100° C. Conversion of(33) to (36) may be accomplished by employing reaction conditionsdiscussed above.

Utilizing reaction conditions described in Schemes 1-5, intermediates(36) may be transformed to compounds (37). Hydrolysis of the esterfunction of (37), followed by coupling of the resulting acids with asuitable amines of formula NHR^(3b)R^(3c) provides compounds of formula(38).

It can be appreciated that the synthetic schemes and specific examplesas illustrated in the synthetic examples section are illustrative andare not to be read as limiting the scope of the invention as it isdefined in the appended claims. All alternatives, modifications, andequivalents of the synthetic methods and specific examples are includedwithin the scope of the claims.

Optimum reaction conditions and reaction times for each individual stepcan vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions can be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Synthetic Examples section. Reactions can be worked up in theconventional manner, e.g. by eliminating the solvent from the residueand further purified according to methodologies generally known in theart such as, but not limited to, crystallization, distillation,extraction, trituration and chromatography. Unless otherwise described,the starting materials and reagents are either commercially available orcan be prepared by one skilled in the art from commercially availablematerials using methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that can not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which canbe found in T. Greene and P. Wuts, Protecting Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention can be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, can be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound is required, it can beobtained by carrying out one of the procedures described herein using anoptically active starting material (prepared, for example, by asymmetricinduction of a suitable reaction step), or by resolution of a mixture ofthe stereoisomers of the compound or intermediates using a standardprocedure (such as chromatographic separation, recrystallization orenzymatic resolution).

Similarly, when a pure geometric isomer of a compound is required, itcan be prepared by carrying out one of the above procedures using a puregeometric isomer as a starting material, or by resolution of a mixtureof the geometric isomers of the compound or intermediates using astandard procedure such as chromatographic separation.

Pharmaceutical Compositions

This invention also provides for pharmaceutical compositions comprisinga therapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier, diluent, or excipient therefor. Thephrase “pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use.

The pharmaceutical compositions that comprise a compound of formula (I),alone or or in combination with a second active pharmaceutical agent,may be administered to the subjects orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrastemal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol and the like), vegetableoils (such as olive oil), injectable organic esters (such as ethyloleate) and suitable mixtures thereof. Proper fluidity can bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents, which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form may be accomplished by dissolving orsuspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In certain embodiments, solid dosage formsmay contain from 1% to 95% (w/w) of a compound of formula I. In certainembodiments, the compound of formula I may be present in the soliddosage form in a range of from 5% to 70% (w/w). In such solid dosageforms, the active compound may be mixed with at least one inert,pharmaceutically acceptable excipient or carrier, such as sodium citrateor dicalcium phosphate and/or a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquatemary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

The pharmaceutical composition may be a unit dosage form. In such formthe preparation is subdivided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampules. Also, the unit dosage form can be a capsule, tablet, cachet, orlozenge itself, or it can be the appropriate number of any of these inpackaged form. The quantity of active component in a unit dosepreparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mgto 100 mg, or from 1% to 95% (w/w) of a unit dose, according to theparticular application and the potency of the active component. Thecomposition can, if desired, also contain other compatible therapeuticagents.

The dose to be administered to a subject may be determined by theefficacy of the particular compound employed and the condition of thesubject, as well as the body weight or surface area of the subject to betreated. The size of the dose also will be determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of a particular compound in a particular subject. Indetermining the effective amount of the compound to be administered inthe treatment or prophylaxis of the disorder being treated, thephysician can evaluate factors such as the circulating plasma levels ofthe compound, compound toxicities, and/or the progression of thedisease, etc. In general, the dose equivalent of a compound is fromabout 1 μg/kg to 100 mg/kg for a typical subject.

For administration, compounds of the formula I can be administered at arate determined by factors that can include, but are not limited to, theLD₅₀ of the compound, the pharmacokinetic profile of the compound,contraindicated drugs, and the side-effects of the compound at variousconcentrations, as applied to the mass and overall health of thesubject. Administration can be accomplished via single or divided doses.

The compounds utilized in the pharmaceutical method of the invention canbe administered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. In certain embodiments, the daily dose range is from about0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varieddepending upon the requirements of the subject, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe practitioner. Treatment may be initiated with smaller dosages, whichare less than the optimum dose of the compound.

Thereafter, the dosage is increased by small increments until theoptimum effect under circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day, if desired.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of formula I may also be administered in the form ofliposomes. Liposomes generally may be derived from phospholipids orother lipid substances. Liposomes are formed by mono- or multi-lamellarhydrated liquid crystals which are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable and metabolizable lipid capable offorming liposomes can be used. The present compositions in liposome formmay contain, in addition to a compound of formula (I), stabilizers,preservatives, excipients and the like. Examples of lipids include, butare not limited to, natural and synthetic phospholipids and phosphatidylcholines (lecithins), used separately or together.

Methods to form liposomes have been described, see example, Prescott,Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33 et seq.

Dosage forms for topical administration of a compound described hereininclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Methods of Use

The compounds of formula I, or pharmaceutically acceptable saltsthereof, and pharmaceutical compositions comprising a compound offormula I, or a pharmaceutically acceptable salt thereof, can beadministered to a subject suffering from a bromodomain-mediated disorderor condition. The term “administering” refers to the method ofcontacting a compound with a subject. Thus, the compounds of formula Ican be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally,parentally, or intraperitoneally. Also, the compounds described hereincan be administered by inhalation, for example, intranasally.Additionally, the compounds of formula I can be administeredtransdermally, topically, via implantation, transdermally, topically,and via implantation. In certain embodiments, the compounds of theformula I may be delivered orally. The compounds can also be deliveredrectally, bucally, intravaginally, ocularly, andially, or byinsufflation. Bromodomain-mediated disorders and conditions can betreated prophylactically, acutely, and chronically using compounds offormula I, depending on the nature of the disorder or condition.Typically, the host or subject in each of these methods is human,although other mammals can also benefit from the administration of acompound of formula I.

A “bromodomain-mediated disorder or condition” is characterized by theparticipation of one or more bromodomains (e.g., BRD4) in the inception,manifestation of one or more symptoms or disease markers, severity, orprogression of a disorder or condition. Accordingly, compounds offormula I may be used to treat cancer, including, but not limited toacoustic neuroma, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia (monocytic, myeloblastic, adenocarcinoma,angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acutet-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladdercancer, brain cancer, breast cancer, bronchogenic carcinoma, cervicalcancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,chronic lymphocytic leukemia, chronic myelocytic (granulocytic)leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.

Further, compounds of formula I may be used to treat inflammatorydiseases, inflammatory conditions, and autoimmune diseases, including,but not limited to: Addison's disease, acute gout, ankylosingspondylitis, asthma, atherosclerosis, Behcet's disease, bullous skindiseases, cardiac myopathy, chronic obstructive pulmonary disease(COPD), Crohn's disease,dermatitis, eczema,giant cell arteritis,glomerulonephritis, heart failure, hepatitis, hypophysitis, inflammatorybowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis,myocarditis,myositis, nephritis, organ transplant rejection,osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa,pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis,rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis,systemic lupus erythematosus, Takayasu's Arteritis, toxic shock,thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo,vasculitis, and Wegener's granulomatosis.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to treat AIDS.

The compounds of formula I can be co-administered to a subject. The term“co-administered” means the administration of two or more differentpharmaceutical agents or treatments (e.g., radiation treatment) that areadministered to a subject by combination in the same pharmaceuticalcomposition or separate pharmaceutical compositions. Thusco-administration involves administration at the same time of a singlepharmaceutical composition comprising two or more pharmaceutical agentsor administration of two or more different compositions to the samesubject at the same or different times.

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to treat acancer, where examples of the agents include, such as radiation,alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors,activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE(Bi-Specific T cell Engager) antibodies, antibody drug conjugates,biologic response modifiers, cyclin-dependent kinase inhibitors, cellcycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (dual variabledomain antibodies), leukemia viral oncogene homolog (ErbB2) receptorinhibitors, growth factor inhibitors, heat shock protein (HSP)-90inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies,immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPs),intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2inhibitors, mammalian target of rapamycin inhibitors, microRNA's,mitogen-activated extracellular signal-regulated kinase inhibitors,multivalent binding proteins, non-steroidal anti-inflammatory drugs(NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP)inhibitors, platinum chemotherapeutics, polo-like kinase (Plk)inhibitors, phosphoinositide-3 kinase (bromodomain) inhibitors,proteosome inhibitors, purine analogs, pyrimidine analogs, receptortyrosine kinase inhibitors, etinoids/deltoids plant alkaloids, smallinhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors,ubiquitin ligase inhibitors, and the like, and in combination with oneor more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand.

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Multispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflomithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194,IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax), ABT-199, and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFRimmunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgAantibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38,EGFR fusion protein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafamib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS 1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyteantigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),sargaramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofiran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (famesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EPO906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafamib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents to treat aninflammatory disease or condition, or autoimmune disease, where examplesof the agents include, such as methotrexate, 6-mercaptopurine,azathioprine sulphasalazine, mesalazine, olsalazinechloroquinine/hydroxychloroquine, pencillamine, aurothiomalate(intramuscular and oral), azathioprine, cochicine, corticosteroids(oral, inhaled and local injection), beta-2 adrenoreceptor agonists(salbutamol, terbutaline, salmeteral), xanthines (theophylline,aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium andoxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil,leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such asprednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asTNFα or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1βconverting enzyme inhibitors, T-cell signalling inhibitors such askinase inhibitors, metalloproteinase inhibitors, sulfasalazine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors and the derivatives p75TNFRIgG (etanercept) and p55TNFRIgG(Lenercept), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines(e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid,hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen,valdecoxib, sulfasalazine, methylprednisolone, meloxicam,methylprednisolone acetate, gold sodium thiomalate, aspirin,triamcinolone acetonide, propoxyphene napsylate/apap, folate,nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenacsodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronatesodium, prednisolone, morphine sulfate, lidocaine hydrochloride,indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl,sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol,naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP,MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-IL15, BIRB-796, SCIO-469,VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists(such as FTY720), PKC family inhibitors (such as Ruboxistaurin orAEB-071) and Mesopram. In certain embodiments, combinations includemethotrexate or leflunomide and in moderate or severe rheumatoidarthritis cases, cyclosporine and anti-TNF antibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory boweldisease with which a compound of Formula (I) of the invention may beco-administered include the following: budenoside; epidermal growthfactor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates;6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors;mesalamine; olsalazine; balsalazide; antioxidants; thromboxaneinhibitors; IL-1 receptor antagonists; anti-IL-13 monoclonal antibodies;anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors;pyridinyl-imidazole compounds; antibodies to or antagonists of otherhuman cytokines or growth factors, for example, TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, andPDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28,CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate;cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide;NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone;phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents;complement inhibitors; adrenergic agents; agents which interfere withsignalling by proinflammatory cytokines such as TNFa or IL-1 (e.g. NIK,IKK, or MAP kinase inhibitors); IL-1β converting enzyme inhibitors; TNFaconverting enzyme inhibitors; T-cell signalling inhibitors such askinase inhibitors; metalloproteinase inhibitors; sulfasalazine;azathioprine; 6-mercaptopurines; angiotensin converting enzymeinhibitors; soluble cytokine receptors and derivatives thereof (e.g.soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) andantiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFi3).Preferred examples of therapeutic agents for Crohn's disease with whicha compound of Formula (I) can be combined include the following: TNFantagonists, for example, anti-TNF antibodies, D2E7 (adalimumab), CA2(infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (etanercept) andp55TNFRIgG (LENERCEPT™) inhibitors and PDE4 inhibitors. A compound ofFormula (I) can be combined with corticosteroids, for example,budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid;olsalazine; and agents which interfere with synthesis or action ofproinflammatory cytokines such as IL-1, for example, IL-1β convertingenzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example,tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine;prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolonesodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis withwhich a compound of Formula (I) may be co-administered include thefollowing: corticosteroids; prednisolone; methylprednisolone;azathioprine; cyclophosphamide; cyclosporine; methotrexate;4-aminopyridine; tizanidine; interferon-μ1a (AVONEX®; Biogen);interferon-β1b (BETASERON®; Chiron/Berlex); interferon α-n3) (InterferonSciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferonβ1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II,GM-CSF, FGF, and PDGF. A compound of Formula (I) can be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. A compound of Formula (I) may also be combined with agents suchas methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil,leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adensosine agonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signalling byproinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 orMAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ).

A compound of Formula (I) may also be co-administered with agents, suchas alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R¹, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitiswith which a compound of Formula (I) can be co-administered include thefollowing: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,methotrexate, azathioprine, minocyclin, prednisone, and anti-TNFantibodies, D2E7 (HUMIRA), CA2 (infliximab), CDP 571, TNFR-Igconstructs, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (LENERCEPT®).

Non-limiting examples of therapeutic agents for asthma with which acompound of Formula (I) may be co-administered include the following:albuterol, salmeterol/fluticasone, montelukast sodium, fluticasonepropionate, budesonide, prednisone, salmeterol xinafoate, levalbuterolHCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, allergy injection, cromolyn sodium,fexofenadine hydrochloride, flunisolide/menthol,amoxicillin/clavulanate, levofloxacin, inhaler assist device,guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,doxycycline hyclate, guaifenesin/d-methorphan,p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride,mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,phenylephrine/cod/promethazine, codeine/promethazine, cefprozil,dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenolsulfate.

Non-limiting examples of therapeutic agents for COPD with which acompound of Formula (I) may be co-administered include the following:albuterol sulfate/ipratropium, ipratropium bromide,salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasonepropionate, prednisone, theophylline anhydrous, methylprednisolonesodium succinate, montelukast sodium, budesonide, formoterol fumarate,triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxonesodium, amoxicillin trihydrate, gatifloxacin, zafirlukast,amoxicillin/clavulanate, flunisolide/menthol,chlorpheniramine/hydrocodone, metaproterenol sulfate,methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir,pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate,tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for psoriasis with which acompound of Formula (I) may be co-administered include the following:calcipotriene, clobetasol propionate, triamcinolone acetonide,halobetasol propionate, tazarotene, methotrexate, fluocinonide,betamethasone diprop augmented, fluocinolone acetonide, acitretin, tarshampoo, betamethasone valerate, mometasone furoate, ketoconazole,pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea,betamethasone, clobetasol propionate/emoll, fluticasone propionate,azithromycin, hydrocortisone, moisturizing formula, folic acid,desonide, pimecrolimus, coal tar, diflorasone diacetate, etanerceptfolate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,methylprednisolone acetate, prednisone, sunscreen, halcinonide,salicylic acid, anthralin, clocortolone pivalate, coal extract, coaltar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone,diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/nalact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen,salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab.

Non-limiting examples of therapeutic agents for psoriatic arthritis withwhich a compound of Formula (I) may be co-administered include thefollowing: methotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), andefalizumab.

Preferred examples of therapeutic agents for SLE (Lupus) with which acompound of Formula (I) may be co-administered include the following:NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam,indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib,valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids,for example, prednisone, prednisolone, budenoside, dexamethasone;cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolatemofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor,for example Cellcept®. A compound of Formula (I) may also be combinedwith agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine,Imuran® and agents which interfere with synthesis, production or actionof proinflammatory cytokines such as IL-1, for example, caspaseinhibitors like IL-1β converting enzyme inhibitors and IL-1ra. Acompound of Formula (I) may also be used with T cell signalinginhibitors, for example, tyrosine kinase inhibitors; or molecules thattarget T cell activation molecules, for example, CTLA-4-IgG or anti-B7family antibodies, anti-PD-1 family antibodies. A compound of Formula(I) can be combined with IL-11 or anti-cytokine antibodies, for example,fonotolizumab (anti-IFNg antibody), or anti-receptor receptorantibodies, for example, anti-IL-6 receptor antibody and antibodies toB-cell surface molecules. A compound of Formula (I) may also be usedwith LJP 394 (abetimus), agents that deplete or inactivate B-cells, forexample, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlySantibody), TNF antagonists, for example, anti-TNF antibodies, D2E7(adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG(etanercept) and p55TNFRIgG (LENERCEPT™).

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in theprevention or treatment of AIDS, where examples of the agents include,HIV reverse transcriptase inhibitors, HIV protease inhibitors,immunomodulators, and other retroviral drugs. Examples of reversetranscriptase inhibitors include, but are not limited to, abacavir,adefovir, didanosine, dipivoxil delavirdine, efavirenz, lamivudine,nevirapine, stavudine zalcitabine, and zidovudine. Examples of proteaseinhibitors include, but are not limited to, amprenavir, indinavir,lopinavir, nelfinavir, ritonavir, and saquinavir.

A compound of Formula (I) may also be co-administered with insulin forthe treatment of type I diabetes.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in theprevention or treatment of AIDS, where examples of the agents include,HIV reverse transcriptase inhibitors, HIV protease inhibitors,immunomodulators, and other retroviral drugs. Examples of reversetranscriptase inhibitors include, but are not limited to, abacavir,adefovir, didanosine, dipivoxil delavirdine, efavirenz, emtricitabine,lamivudine, nevirapine, rilpivirine, stavudine, tenofovir, zalcitabine,and zidovudine. Examples of protease inhibitors include, but are notlimited to, amprenavir, atazanavir, darunavir, indinavir, fosamprenavir,lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. Examplesof other retroviral drugs include, but are not limited to, elvitegravir,enfuvirtide, maraviroc and raltegravir.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in thetreatment of obesity, where examples of the agents include orlistat.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in thetreatment of type II diabetes, where examples of the agents include,alpha glucosidase inhibitors, insulin, metformin, sulfonylureas (e.g.,carbutamide, acetohexamide, chlorpropamide, glibenclamide, glibomuride,gliclazide, glimepiride, glipizide, gliquidone, glisoxepide,glyclopyramide, tolbutamide, and tolazamide), nonsulfonylureas (e.g.,nateglinide, and repaglinide), and thiazolidinediones (e.g.,pioglitazone).

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to prevent ortreat type II diabetes, hepatic steatosis, insulin resistance, metabolicsyndrome and related disorders, where examples of the agents include,but are not limited to, insulin and insulins that have been modified toimprove the duration of action in the body; agents that stimulateinsulin secretion such as acetohexamide, chlorpropamide, glyburide,glimepiride, glipizide, glicazide, glycopyramide, gliquidone,rapaglinide, nataglinide, tolazamide and tolbutamide; agents that areglucagon-like peptide agonists such as exanatide, liraglutide andtaspoglutide; agents that inhibit dipeptidyl-peptidase IV such asvildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin andseptagliptin; agents that bind to the peroxisome proliferator-activatedreceptor gamma such as rosiglitazone and pioglitazone; agents thatdecrease insulin resistance such as metformin; agents that reduceglucose absorbance in the small intestine such as acarbose, miglitol andvoglibose.

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to prevent ortreat acute kidney disorders and chronic kidney diseases, where examplesof the agents include, but are not limited to, dopamine, diuretics suchas furosemide, bumetanide, thiazide and the like, mannitol, calciumgluconate, sodium bicarbonate, albuterol, paricalcitol, doxercalciferol,and cinacalcet.

The following Examples may be used for illustrative purposes and shouldnot be deemed to narrow the scope of the invention.

EXAMPLES Example 14-(cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 1a(E)-2-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-N,N-dimethylethenamine

5-Bromo-2-methoxy-4-methyl-3-nitropyridine (15.0 g, 60.7 mmol) wasdissolved in dimethylformamide (300 mL), and lithium methanolate (6.07mL, 6.07 mmol, 1 M) was added. The reaction mixture was heated at 100°C. To this mixture was added 1,1-dimethoxy-N,N-dimethylmethanamine (64.5mL, 486 mmol) over 10 minutes. The reaction mixture was stirred at 95°C. for 16 hours. The reaction mixture was cooled to ambient temperatureand water was added carefully (300 mL, exothermic). The resultingprecipitate was collected by vacuum filtration, washed with water, anddried to provide the title compound (13.9 g, 45.9 mmol, 76% yield).

Example 1b 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

Example 1a (13.9 g, 45.8 mmol) and ethyl acetate (150 mL) were added toRa—Ni 2800 (pre-washed with ethanol), water slurry (6.9 g, 118 mmol) ina stainless steel pressure bottle and stirred for 30 minutes at 30 psiand ambient temperature. The reaction mixture was filtered, andconcentrated. The residue was triturated with dichloromethane, and thesolid filtered to provide the title compound (5.82 g). The mother liquorwas concentrated and the residue triturated again with dichloromethaneand filtered to provide an additional 1.63 g of the title compound.Total yield=7.45 g, 72% yield

Example 1c 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

A solution of Example 1b (7.42 g, 32.7 mmol) in dimethylformamide (235mL) was stirred at ambient temperature. To this solution was addedsodium hydride (1.18 g, 1.96 g of 60% dispersion in oil, 49.0 mmol), andthe reaction mixture was stirred for 10 minutes. P-toluenesulfonylchloride (9.35 g, 49.0 mmol) was then added portion-wise, and themixture was stirred at ambient temperature under nitrogen for 16 hours.The reaction mixture was quenched carefully with water and the resultingbeige solid collected by vacuum filtration on a Buchner funnel, andwashed with water. The solid was collected and dried in a vacuum oven at50° C. to provide 12.4 g (100%) of the title compound.

Example 1d 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A solution of Example 1c (12.4 g, 32.6 mmol) in dioxane (140 mL) wasstirred at ambient temperature. To this solution was added 4M HCl indioxane (140 mL). The reaction mixture was stirred at 40° C. for 16hours. The reaction mixture was cooled to ambient temperature andconcentrated. The residue was triturated with diethylether, filtered,and rinsed with additional diethylether and dried to provide the titlecompound (11.23 g, 30.6 mmol, 94% yield) as a beige solid.

Example 1e 4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil dispersion)was added to a stirring solution of Example 1d (11.2 g, 30.4 mmol) indimethylformamide (217 mL) under nitrogen. After 30 minutes, iodomethane(2.27 mL, 36.5 mmol) was added and the solution was stirred at ambienttemperature for 3 hours. Upon addition of water (250 mL) a precipitateformed. The precipitate was collected by vacuum filtration, rinsed withwater (50 mL) and dried in a vacuum oven at 55° C. overnight to provide11.2 g of the title compound (96%).

Example 1f6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 1e (6.55 g, 17.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (8.73 g,34.4 mmol), potassium acetate (3.71 g, 37.8 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.393 g, 0.430 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-PHOS, 0.819 g,1.72 mmol) were combined and sparged with argon for 1 hour withstirring. Dioxane (86 mL) was sparged with nitrogen for 1 hour,transferred via cannula under nitrogen to the solid components, and themixture was heated under argon at 80° C. for 5 hours. The reactionmixture was cooled to ambient temperature, partitioned between ethylacetate and water, and filtered through Celite. The ethyl acetate layerwas washed twice with saturated aqueous sodium chloride, dried(anhydrous sodium sulfate), filtered and concentrated. The residue waspurified by chromatography (silica gel, 25-80% ethyl acetate in hexane).The resulting material from chromatography was triturated with a minimalamount of hexanes (30 mL) and the particulate solid was collected byfiltration, rinsed with a minimal amount of hexanes and dried toconstant mass to afford the title compound (5.4 g, 73%).

Example 1g (3-bromo-4-fluorophenyl)(isopropyl)sulfane

A 250 mL round bottomed flask was charged with3-bromo-4-fluorobenzenethiol (3.89 g, 18.79 mmol), sodium hydroxide(3.95 mL, 19.73 mmol) and methanol. The reaction mixture was stirred at0° C. for 10 minutes. To this solution was added 2-iodopropane (3.83 g,22.54 mmol). The reaction mixture was stirred at ambient temperature for6 hours. The solvent was removed, and the residue was partitionedbetween water and ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate three times. The combined organic layers werewashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated to provide the titlecompound.

Example 1h 2-bromo-1-fluoro-4-(isopropylsulfonyl)benzene

A 500 mL round bottomed flask was charged with Example 1g (4.0 g, 16.06mmol) and dichloromethane (200 mL). mCPBA (8.71 g, 35.3 mmol) was added.The reaction mixture was stirred at ambient temperature for 6 hours. Thereaction mixture was filtered, and the solids were washed by additionaldichloromethane. The filtrate was washed with 10% NaOH (50 mL, twice),then saturated sodium bicarbonate. The organic layer was concentrated,and the residue was purified by flash chromatography on silica gel (15%ethyl acetate in heptanes) to provide the title compound.

Example 1i 2-bromo-N-(cyclopropylmethyl)-4-(isopropylsulfonyl)aniline

A mixture of Example 1h (0.562 g, 2 mmol) and cyclopropylmethanamine(0.427 g, 6.00 mmol) in dioxane (10 mL) was heated at 100° C. overnight.The solvent was removed, and the residue was purified by flashchromatography (50% ethyl acetate in heptanes) to provide the titlecompound.

Example 1j4-(2-((cyclopropylmethyl)amino)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 1f (0.086 g, 0.2 mmol), Example 1i (0.066 g, 0.2mmol), cesium fluoride (0.091 g, 0.600 mmol), andtetrakistriphenylphosphine palladium (0.012 g, 10.00 μmol) indimethoxyethane (2 mL) and methanol (1 mL) was heated under microwaveconditions (120 C, 40 min). The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered and concentrated. The residue was purified by reverse phaseHPLC (C18, CH₃CN/water (0.1% TFA), 0-100% gradient) to provide the titlecompound.

Example 1k4-(cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 4 mL vial was charged with Example 1j (0.0106 g, 0.027 mmol),paraformaldehyde (3.98 mg, 0.133 mmol) and methanol (0.265 mL) to give awhite suspension. Hydrochloric acid (4N in dioxane, 0.133 mL, 0.531mmol) was added. The vial was closed and the reaction mixture was heatedat 90° C. for 1 hour. The reaction mixture was cooled to ambienttemperature and diluted with ether. The resulting suspension wasfiltered, and the solid was rinsed with ether, collected, and dried in a60° C. vacuum oven overnight to provide a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ 11.83 (s, 1H), 8.04 (d, J=2.04 Hz, 1H), 7.65 (m, 2H), 7.41(d, J=8.82 Hz, 1H), 7.18 (d, J=2.03 Hz, 1H), 4.26 (s, 2H), 3.64 (s, 3H),3.49 (m, 1H), 3.03 (d, J=6.1 Hz, 2H), 1.20 (d, J=6.78 Hz, 6H), 0.90 (m,1H), 0.41 (m, 2H), 0.09 (q, J=4.63 Hz, 2H). MS (ESI+) m/z 412.1 (M+H)⁺.

Example 24-(cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 2a (3-bromo-4-fluorophenyl)(ethyl)sulfane

A mixture of 3-bromo-4-fluorobenzenethiol (3.89 g, 18.79 mmol) andsodium hydroxide (3.95 mL, 19.73 mmol) in methanol was stirred at 0° C.for 10 minutes. To this solution was added iodoethane (1.803 mL, 22.54mmol). The reaction mixture was stirred at ambient temperature for 6hours. The solvent was removed, and the residue was partitioned betweenwater and ethyl acetate. The aqueous layer was extracted with additionethyl acetate three times. The combined organic layers were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated to give the title compound (4.35 g,18.50 mmol, 98% yield).

Example 2b 2-bromo-4-(ethylsulfonyl)-1-fluorobenzene

Example 2a (4.4 g, 18.71 mmol) in dichloromethane (250 mL) was cooled to0° C. To this solution was treated with mCPBA (10.15 g, 41.2 mmol)portionwise. The reaction mixture was stirred at ambient temperature for6 hours. The solid from the reaction mixture was removed by filtration.The filtrate was washed with saturated aqueous sodium bicarbonateseveral times. The aqueous layer was then extracted with additionaldichloromethane three times. The combined organic layers were washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography on silica gel eluting with 15% ethyl acetate/hexanes toafford the title compound (4.4 g, 16.47 mmol, 88% yield).

Example 2c 2-bromo-N-(cyclopropylmethyl)-4-(ethylsulfonyl)aniline

Example 2c was prepared according to the procedure used for thepreparation of Example 1i, substituting Example 2b for Example 1h, toprovide the title compound.

Example 2d4-{2-[(cyclopropylmethyl)amino]-5-(ethylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 2d was prepared according to the procedure used for thepreparation of Example 1j, substituting Example 2c for Example 1i, toprovide the title compound.

Example 2e4-(cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 2d (0.03 g, 0.078 mmol) and paraformaldehyde (0.012g, 0.389 mmol) in methanol (0.778 mL) was treated with 4M hydrogenchloride (0.389 mL, 1.557 mmol). The mixture was heated at 90° C. for 1hour, cooled, and concentrated. Purification by chromatography (silicagel, 1-5% methanol in dichloromethane) afforded the title compound(0.022 g, 71%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.51 (s, 1H), 8.08 (d,J=2.14 Hz, 1H), 7.66 (dd, J=8.54, 2.14 Hz, 1H), 7.58 (s, 1H), 7.44 (d,J=8.54 Hz, 1H), 7.12 (d, J=2.75 Hz, 1H), 4.27 (s, 2H), 3.64 (s, 3H),3.28 (d, J=7.32 Hz, 2H), 3.03 (d, J=6.10 Hz, 2H), 1.18 (t, J=7.32 Hz,3H), 0.83-0.98 (m, 1H), 0.33-0.43 (m, 2H), 0.04-0.11 (m, 2H). MS (ESI+)m/z 398 (M+H)⁺.

Example 34-(cyclopropylmethyl)-3-ethyl-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 2d (0.045 g, 0.117 mmol) and propionaldehyde (0.136g, 2.335 mmol) in methanol (1.167 mL) was treated with 4M hydrogenchloride (0.584 mL, 2.34 mmol). The mixture was heated at 90° C. for 3hours, cooled and concentrated. The residue was dissolved in ethylacetate, washed with 5% aqueous sodium bicarbonate, saturated aqueoussodium chloride, dried (anhydrous Na₂SO₄), filtered and concentrated.Purification by chromatography (silica gel, 0-5% methanol indichloromethane) afforded a solid that was triturated in a minimalamount of 30% ethyl acetate in heptanes to afford the title compound(0.017 g, 34%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.83 (s, 1H), 8.05 (s, 1H),7.70 (s, 1H), 7.65 (dd, J=8.31, 2.20 Hz, 1H), 7.41 (d, J=8.48 Hz, 1H),7.14 (d, J=2.37 Hz, 1H), 4.37 (s, 1H), 3.64 (s, 3H), 3.37 (q, J=7.29 Hz,2H), 3.13 (s, 1H), 2.93 (s, 1H), 1.41-1.59 (m, 1H), 1.14 (t, J=7.29 Hz,3H), 1.03-1.09 (m, 1H), 0.86 (t, J=6.78 Hz, 3H), 0.77-0.88 (m, 1H), 0.36(d, J=8.14 Hz, 2H), 0.03-0.10 (m, 2H). MS (ESI+) m/z 426 (M+H)⁺.

Example 410-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 4a4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

2-bromo-4-(methylsulfonyl)aniline (1.0 g, 4.00 mmol), Example if (1.712g, 4.00 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.110 g, 0.120mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane(0.117 g, 0.400 mmol) and sodium carbonate (1.483 g, 13.99 mmol) werecombined and sparged with argon for 15 minutes.

Meanwhile a solution of 4:1 dioxane/water (26 mL) was sparged withnitrogen for 15 minutes and transferred by syringe into the reactionvessel under argon. The mixture was stirred for 3 hours at 60° C.,cooled, diluted into 100 mL of water and the resulting solid wascollected by filtration, washed with water and dried to constant mass toafford the title compound (2.05 g, 100%).

Example 4b4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 4b was prepared according to the procedure used for thepreparation of Example 5e, substituting Example 4a for Example 5d.Purification by trituration in dichloromethane afforded the titlecompound (0.55 g, 82%).

Example 4c10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 4c was prepared according to the procedure used for thepreparation of Example 1k, substituting Example 4b for Example 1j, toafford the title compound as the HCl salt (0.046 g, 98%). ¹H NMR (400MHz, DMSO-d₆) δ 11.53 (s, 1H), 8.14 (d, J=2.14 Hz, 1H), 7.63 (s, 1H),7.56 (dd, J=8.39, 2.29 Hz, 1H), 7.23 (d, J=8.54 Hz, 1H), 7.13 (d, J=2.44Hz, 1H), 4.23 (s, 2H), 3.65 (s, 3H), 3.17 (s, 3H). MS (ESI+) m/z 330(M+H)⁺.

Example 510-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 5a 1-((methylsulfonyl)methyl)-4-nitrobenzene

To a solution of 4-nitrobenzyl bromide (10.02 g, 46.4 mmol) inN,N-dimethylformamide (25 mL) was added sodium methanesulfinate (7.10 g,69.6 mmol). The reaction mixture was stirred at 65° C. for 1 hour. Thereaction mixture was cooled to ambient temperature and diluted withwater. The resulting suspension was stirred 10 minutes and filteredthrough a medium frit to provide the title compound.

Example 5b 4-((methylsulfonyl)methyl)aniline

Example 5a (8.2 g, 38.1 mmol) and tetrahydrofuran (200 mL) were added to5% Pd/C, wet (1.6 g, 0.376 mmol) in a 50 mL pressure bottle and stirredfor 2 hours at 30 psi and 50° C. The mixture was filtered through anylon membrane and washed with a small amount of tetrahydrofuran andmethanol. The solvent was removed to provide the title compound.

Example 5c 2-iodo-4-((methylsulfonyl)methyl)aniline

To a solution of Example 5b (3.80 g, 20.51 mmol) inN,N-dimethylformamide (103 mL) was added N-iodosuccinimide (5.08 g,22.56 mmol). The reaction mixture was stirred at ambient temperature for1 hour. The reaction mixture was quenched with 150 mL 10% sodiumthiosulfate and 100 mL saturated sodium bicarbonate. The reactionmixture was extracted 3× with ethyl acetate. The combined organic layerswere washed with saturated aqueous sodium chloride and concentrated.Water was added, and the resulting suspension was stirred at ambienttemperature for 10 minutes. The suspension was filtered and driedovernight to provide the title compound.

Example 5d4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 100 mL round-bottomed flask was charged with Example 5c (0.160 g,0.514 mmol), Example 1f (0.200 g, 0.467 mmol), potassium phosphate(0.446 g, 2.101 mmol), tris(dibenzylideneacetone)dipalladium (II) (0.021g, 0.023 mmol), and1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.023 g,0.079 mmol). The solids were flow purged with nitrogen for 30 minutes.Degassed dioxane (3.74 mL) and water (0.934 mL) were added. The reactionmixture was heated at 60° C. for 3 hours. The reaction mixture wascooled to ambient temperature and diluted with water. The resultingsuspension was filtered, and the brown solid was collected.

Example 5e4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 250 mL round-bottomed flask was charged with Example 5d (0.230 g,0.474 mmol), potassium hydroxide (0.691 g, 12.32 mmol),N,N,N-trimethylhexadecan-1-aminium bromide (8.63 mg, 0.024 mmol),dioxane (3.55 mL) and water (1.18 mL) to give a light yellow solution.The reaction mixture was heated at 90° C. overnight. The reactionmixture was cooled to ambient temperature and treated with 1Nhydrochloric acid to achieve a pH of 1. The reaction mixture wasextracted with twice with ethyl acetate. The combined organic layerswere washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was purifiedby flash chromatography (0%-10% methanol in dichloromethane) to providethe title compound.

Example 5f10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 20 mL microwave tube was charged with Example 5e (0.0397 g, 0.120mmol), paraformaldehyde (0.018 g, 0.599 mmol) and methanol (1.198 mL) togive a white suspension. Hydrochloric acid (4N in dioxane 0.599 mL,2.396 mmol) was added. The reaction mixture was heated at 90° C. for 1hour. The reaction mixture was cooled to ambient temperature and dilutedwith ether and ethyl acetate. The reaction mixture was washed withsaturated sodium bicarbonate and saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate, filtered and concentrated. Theresidue was purified by flash chromatography (0%-10% methanol indichloromethane) to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 11.75 (s, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.50 (s, 1H),7.07-7.15 (m, 2H), 7.00 (d, J=8.2 Hz, 1H), 4.37 (s, 2H), 4.11 (d, J=3.2Hz, 2H), 3.61 (s, 3H), 2.90 (s, 3H). MS (ESI+) m/z 344.4 (M+H)⁺.

Example 64-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 6aN-(cyclopropylmethyl)-2-iodo-4-((methylsulfonyl)methyl)aniline

Example 5c (0.200 g, 0.643 mmol) and cyclopropanecarbaldehyde (0.062 mL,0.836 mmol) were suspended in dichloromethane (3.21 mL) and methanol(3.21 mL). Acetic acid (0.368 mL, 6.43 mmol) was added. The reactionmixture was heated at 50° C. for 30 minutes, then cooled to ambienttemperature. Polymer supported cyanoborohydride (0.817 g, 1.928 mmol)was added. The reaction mixture was stirred at ambient temperatureovernight. Cyclopropanecarbaldehyde (0.062 mL, 0.836 mmol) was added,and the reaction mixture was stirred at ambient temperature for 2 hours.The reaction mixture was filtered, thoroughly rinsed withdichloromethane, and concentrated. The residue was purified by flashchromatography (20-100% ethyl acetate/heptane) to provide the titlecompound.

Example 6b4-(2-((cyclopropylmethyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 250 mL round-bottomed flask was charged with Example 6a (0.1546 g,0.423 mmol), Example if (0.404 g, 1.905 mmol),tris(dibenzylideneacetone)dipalladium (II) (0.019 g, 0.021 mmol), and1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.021 g,0.072 mmol). The solids were sparged with nitrogen for 30 minutes.Degassed dioxane (3.40 mL) and water (0.850 mL) were added. The reactionwas heated at 60° C. for 3 hours. The reaction was cooled to roomtemperature and partitioned between ethyl acetate and water. The organiclayer was washed with saturated aqueous sodium chloride solution, driedover magnesium sulfate, filtered and concentrated. The residue waspurified by flash chromatography (0-5% methanol/dichloromethane) toprovide the title compound (0.211 g, 92% yield).

Example 6c4-{2-[(cyclopropylmethyl)amino]-5-[(methylsulfonyl)methyl]phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

A 250 mL round-bottomed flask was charged with Example 6b (0.211 g,0.391 mmol), potassium hydroxide (0.570 g, 10.17 mmol), andN,N,N-trimethylhexadecan-1-aminium bromide (7.12 mg, 0.020 mmol),dioxane (2.93 mL) and water (0.977 mL). The reaction mixture was heatedat 90° C. for 2.5 hours. The reaction mixture was cooled to ambienttemperature and treated with 1N HCl to achieve a pH of about 7. Thereaction mixture was extracted with ethyl acetate (2×). The combinedorganic extracts were washed with saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, filtered andconcentrated to provide the title compound (0.0886 g, 59% yield).

Example 6d4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 5 mL microwave tube was charged with Example 6c (0.027 g, 0.070 mmol),paraformaldehyde (0.032 g, 0.350 mmol) and methanol (0.700 mL) to give awhite suspension. 4N HCl in dioxane (0.350 mL, 1.401 mmol) was added.The tube was closed and the reaction was heated at 90° C. for 1 hour.The reaction was cooled to room temperature and diluted with ether. Theresulting suspension was filtered, and the solid was rinsed with ether,collected, and dried in a 60° C. vacuum oven overnight to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆ 90° C.) δ 11.64 (m, 1H), 7.79(s, 1H), 7.57 (s, 1H), 7.39-7.52 (m, 1H), 7.32 (d, J=7.1 Hz, 1H), 7.19(s, 1H), 4.44 (s, 2H), 4.40 (s, 2H), 3.55 (s, 1H), 2.84-2.92 (m, 5H),0.85 (s, 1H), 0.35 (dd, J=7.9, 1.1 Hz, 2H), −0.02-0.04 (m, 2H). MS(ESI+) m/z 398.0 (M+H)⁺.

Example 7 ethyl4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate

A 5 mL microwave tube was charged with Example 6c (0.027 g, 0.070 mmol),ethyl glyoxylate (0.069 mL, 0.350 mmol) and ethanol (0.700 mL) to give awhite suspension. Hydrochloric acid (4N in dioxane, 0.350 mL, 1.401mmol) was added. The suspension became a colorless solution. The vialwas closed and the reaction mixture was heated at 90° C. for 1 hour. Thereaction mixture was cooled to ambient temperature and diluted withether. A white precipitate formed. The resulting suspension wasfiltered, and the solid was rinsed with ether, collected, and dried in a60° C. vacuum oven overnight. The residue was purified by reverse phaseHPLC (C18, CH₃CN/water (0.1% TFA), 0-100% gradient) to afford the titlecompound (0.0090 g, 27%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.91 (s, 1H),7.64 (s, 1H), 7.52 (s, 1H), 7.21 (dd, J=13.0, 5.3 Hz, 4H), 5.39 (s, 1H),4.42 (m, 2H), 3.83 (s, 2H), 3.83 (s, 2H), 3.63 (s, 3H), 2.86 (s, 3H),0.93 (t, J=7.2 Hz, 3H), 0.83 (m, 1H), 0.29-0.46 (m, 2H), 0.07 (m, 2H).MS (ESI+) m/z 470.0 (M+H)⁺.

Example 84-(4-fluorophenyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 8a4-(2-amino-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 1f (1.71 g, 4.00 mmol), 2-bromo-4-(methylsulfonyl)aniline (1.00g, 4.00 mmol), tris(dibenzylideneacetone)dipalladium (0.110 g, 0.120mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante(0.117 g, 0.400 mmol) and sodium carbonate (1.48 g, 14.0 mmol) werecombined and purged with argon for 15 minutes. A mixture of dioxane(21.3 mL) and water (5.3 mL) was purged with nitrogen for 15 minutes andtransferred to the reaction vessel. The reaction mixture was heated at60° C. for 3 hours, cooled to ambient temperature and diluted withwater. The resulting solid was filtered, washed with water and dried toafford the title compound (2.06 g, quantitative yield).

Example 8b4-(2-((4-fluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 8a (47.2 mg, 0.100 mmol), 1-bromo-4-fluorobenzene (17.5 mg,0.100 mmol), diacetoxypalladium (0.9 mg, 4 μmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (3.8mg, 8.0 μmol) and cesium carbonate (45.6 mg, 0.140 mmol) were combinedin a mixture of toluene (1.6 mL) and tert-butanol (0.4 mL). The reactionmixture was heated in a microwave reactor at 150° C. for 15 minutes. Thereaction mixture was partitioned with ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride, driedwith anhydrous sodium sulfate, treated with 3-mercaptopropylfunctionalized silica gel, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 2-4% methanol indichloromethane) to provide the title compound (30 mg, 53%).

Example 8c4-{2-[(4-fluorophenyl)amino]-5-(methylsulfonyl)phenyl}-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

Example 8b (28 mg, 0.050 mmol), potassium hydroxide (41.7 mg, 0.743mmol) and cetyltrimethylammonium bromide (0.90 mg, 2.5 μmol) werecombined in a mixture of tetrahydrofuran (2 mL) and water (1 mL). Thereaction mixture was heated at 100° C. for 20 hours and then cooled toambient temperature. To this mixture was added water, and the pH wasadjusted to pH 7 by the addition of 1M HCl. The mixture was extractedwith ethyl acetate and the organic layer was washed with saturatedaqueous sodium chloride twice, dried with anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 2-4% methanol in dichloromethane) to providethe title compound (13 mg, 64%).

Example 8d4-(4-fluorophenyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 2 mL vial was charged with Example 8c (8.0 mg, 0.019 mmol),paraformaldehyde (5.8 mg, 0.19 mmol) and methanol (0.5 mL). To thissuspension was added 4M HCl in dioxane (0.097 mL, 0.39 mmol). The vialwas closed and stirred at 90° C. for 4 hours. The reaction mixture wascooled to ambient temperature and concentrated. To this residue wasadded water, and the pH was adjusted to pH 7 by addition of saturatedaqueous sodium bicarbonate. The residue was sonicated for 5 minutes andfiltered to afford the title compound (7.0 mg, 85%). ¹H NMR (300 MHz,DMSO-d₆) δ 11.88 (d, J=1.70 Hz, 1H) 8.37 (d, J=2.37 Hz, 1H) 7.88 (dd,J=8.14, 2.37 Hz, 1H) 7.85 (s, 1H) 7.53 (d, J=8.14 Hz, 1H) 7.35 (d,J=2.37 Hz, 1H) 6.75-6.91 (m, 2H) 6.43-6.51 (m, 2H) 4.80 (s, 2H) 3.59 (s,3H) 3.36 (s, 3H). MS (ESI+) m/z 424 (M+H)⁺.

Example 94-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 9a 1-bromo-4-((methylsulfonyl)methyl)benzene

A 250 mL round-bottomed flask was charged with 4-bromobenzyl bromide(5.000 g, 20.01 mmol) and N,N-dimethylformamide (10.81 mL) to give acolorless solution. Sodium methanesulfinate (3.06 g, 30.0 mmol) wasadded. The reaction mixture was stirred at 65° C. for 1 hour. Thereaction mixture was cooled to room temperature and diluted with water.The resulting suspension was stirred for 10 minutes and filtered. Thesolid was rinsed with water and dried under house vacuum over theweekend to provide the title compound (4.75 g, 95% yield).

Example 9b 4-fluoro-N-(4-((methylsulfonyl)methyl)phenyl)aniline

A 100 mL microwave tube was charged with 4-fluoroaniline (0.388 mL, 4.04mmol), Example 9a (1.0065 g, 4.04 mmol), diacetoxypalladium (0.036 g,0.162 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.154g, 0.323 mmol), cesium carbonate (1.843 g, 5.66 mmol), toluene (20.20mL) and t-butanol (4.04 mL) to give a yellow suspension. The tube wassealed, and the reaction mixture was heated in a Milestone Ethosmicrowave reactor to 150° C. for 15 minutes fixed hold time. Thereaction mixture was filtered through a 10 g Celite SPE column andrinsed with ethyl acetate. The filtrate was washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered and concentrated onto silica gel. The crude product waspurified by flash chromatography (20-100% ethyl acetate in heptanes) toprovide the title compound as an off white solid.

Example 9c 2-bromo-N-(4-fluorophenyl)-4-((methylsulfonyl)methyl)aniline

A 250 mL round-bottomed flask was charged with Example 9b (1.32 g, 4.73mmol) and acetic acid (47.3 mL) to give a white suspension. The reactionmixture was cooled in a water bath. N-bromosuccinimide (0.807 g, 4.54mmol) was added in two portions 10 minutes apart. The reaction mixturewas stirred at ambient temperature for 1.5 hours. The reaction mixturewas quenched with 10% sodium thiosulfate (40 mL) and diluted with 2Nsodium hydroxide and ethyl acetate. The layers were separated, and theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered and concentrated onto silicagel. The crude product was purified by flash chromatography (20-70%ethyl acetate in heptanes) to provide the title compound as a whitesolid.

Example 9d4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 250 mL round-bottomed flask was charged with Example 9c (1.9175 g,5.35 mmol), Example if (2.084 g, 4.87 mmol), sodium carbonate (1.805 g,17.03 mmol), tris(dibenzylideneacetone)dipalladium (II) (0.223 g, 0.243mmol), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane(0.242 g, 0.827 mmol). The solids were sparged with nitrogen for 30minutes. Degassed dioxane (38.9 mL) and water (9.73 mL) were added. Thereaction mixture was heated at 60° C. for 3 hours. The reaction mixturewas cooled to room temperature and partitioned between ethyl acetate andwater. The organic layer was washed with saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate andmercaptopropyl silica gel, filtered and concentrated. The residue wastaken up into dichloromethane, triturated with ether, and filtered toprovide the title compound (2.13 g, 75% yield).

Example 9e4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 250 mL round-bottomed flask was charged with Example 9d (2.1251 g,3.67 mmol), potassium hydroxide (5.35 g, 95 mmol), andN,N,N-trimethylhexadecan-1-aminium bromide (0.067 g, 0.183 mmol),dioxane (55.0 mL) and water (18.33 mL). The reaction mixture was heatedat 90° C. for 2.5 hours. The reaction mixture was cooled to roomtemperature and diluted to 500 mL (total volume) with water. Theresulting suspension was filtered, and the solid was rinsed with waterand allowed to dry on the frit for 1.5 hours. The solid was collectedand dried in a 60° C. vacuum oven overnight to provide the titlecompound (1.24 g, 80% yield).

Example 9f4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 20 mL microwave tube was charged with Example 9e (0.5195 g, 1.221mmol), paraformaldehyde (0.550 g, 6.10 mmol) and methanol (12.21 mL) togive a white suspension. Hydrochloric acid (4N in dioxane, 6.10 mL,24.42 mmol) was added. The vial was closed and the reaction mixture washeated at 90° C. for 1 hour. The reaction mixture was cooled to ambienttemperature. The reaction mixture was partitioned betweendichloromethane and saturated sodium bicarbonate. The aqueous layer wasextracted 3× with dichloromethane. The combined organic layers werewashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was taken upinto dichloromethane and triturated with ether. The resulting slurry wasstirred for 10 minutes, and filtered. The white solid was rinsed withether, collected, and dried in a 60° C. vacuum oven overnight to providethe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 11.90-11.84 (m, 1H),7.91 (d, J=1.9 Hz, 1H), 7.61 (s, 1H), 7.44 (dd, J=8.0, 1.9 Hz, 1H), 7.33(d, J=4.9 Hz, 2H), 6.80 (t, J=8.8 Hz, 2H), 6.35-6.46 (m, 2H), 4.56 (m,2H), 3.55 (s, 3H), 3.00 (s, 3H). MS (ESI+) m/z 438.2 (M+H)⁺.

Example 104-(cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-7-sulfonamideExample 10a 5-bromo-6-((cyclopropylmethyl)amino)pyridine-3-sulfonamide

A mixture of 5-bromo-6-chloropyridine-3-sulfonamide (0.272 g, 1 mmol)and cyclopropylmethanamine (0.213 g, 3.00 mmol) in dioxane (5 mL) washeated at 100° C. overnight. The reaction mixture was partitionedbetween water and ethyl acetate. The organic layer was separated, andthe aqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel, eluting with 60% ethyl acetate inhexanes to give 0.298 g (97%) of the title compound.

Example 10b6-[(cyclopropylmethyl)amino]-5-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridine-3-sulfonamide

Example 10b was prepared according to the procedure used for thepreparation of Example 1j, substituting Example 10a for Example 1i, toprovide the title compound.

Example 10c4-(cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-7-sulfonamide

Example 10c was prepared according to the procedure used for thepreparation of Example 1k, substituting Example 10b for Example 1j, toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 11.90 (s, 1H),8.46 (d, J=2.44 Hz, 1H), 8.31 (d, J=2.44 Hz, 1H), 7.51 (s, 1H), 7.31 (s,2H), 7.22 (d, J=2.44 Hz, 1H), 4.39 (s, 2H), 3.63 (s, 3H), 3.48 (d,J=6.41 Hz, 2H), 0.45 (dd, J=8.09, 1.68 Hz, 2H), 0.25 (dd, J=4.88 Hz,2H). MS (ESI+) m/z 386.1 (M+H)⁺.

Example 114-(4-fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-oneExample 11a 3-bromo-N-(4-fluorophenyl)-5-methylpyridin-2-amine

2-Amino-3-bromo-5-methylpyridine (0.468 g, 2.5 mmol),4-fluoroiodobenzene (0.555 g, 2.500 mmol), diacetoxypalladium (0.017 g,0.075 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)(0.043 g, 0.075 mmol) and sodium 2-methylpropan-2-olate (0.336 g, 3.50mmol) were combined in t-butanol (10.00 mL) and sparged with argon for10 minutes. The mixture was heated for 60 minutes at 85° C., cooled,diluted with 50 mL ethanol and filtered through Celite to remove solids.The filtrate was concentrated and diluted with ethyl acetate. Theorganic layer was washed with water, saturated aqueous sodium chloride,dried (anhydrous sodium sulfate), treated with 3-mercaptopropylfunctionalized silica, filtered and concentrated. Purification bychromatography (silica gel, 0-25% ethyl acetate in heptanes) affordedthe title compound (0.317 g, 45%).

Example 11b4-(2-((4-fluorophenyl)amino)-5-methylpyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 11a (0.3 g, 1.067 mmol), Example if (0.457 g, 1.067 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.029 g, 0.032 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.031 g,0.107 mmol) and sodium carbonate (0.396 g, 3.74 mmol) were combined andsparged with argon for 15 minutes. A solution of 4:1 dioxane/water (12mL) was sparged with nitrogen for 15 minutes and transferred by syringeinto the reaction vessel under argon. The mixture was stirred for 1 hourat 60° C., cooled and partitioned into 100 mL of water and 120 mL ofdichloromethane. The organic layer was washed with water, saturatedaqueous sodium chloride, dried (anhydrous sodium sulfate), treated with3-mercaptopropyl functionalized silica, filtered and concentrated.Purification by trituration in 9:1 heptane/ethyl acetate afforded thetitle compound (0.46 g, 86%).

Example 11c4-(2-((4-fluorophenyl)amino)-5-methylpyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 11c was prepared according to the procedure used for thepreparation of Example 5e, substituting Example 11b for Example 5d.Purification by trituration in dichloromethane afforded the titlecompound (0.20 g, 63%).

Example 11d4-(4-fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 11c (0.05 g, 0.144 mmol), paraformaldehyde (0.043g, 1.435 mmol) and 4M hydrogen chloride (1.076 mL, 4.31 mmol) inmethanol (1.435 mL) in a sealed microwave tube was heated by microwaveat 130° C. for 2 hours. The mixture was concentrated and the residue waspartitioned between ethyl acetate and 5% aqueous sodium bicarbonate. Theorganic layer was washed with saturated aqueous sodium chloride, dried(anhydrous sodium sulfate), filtered and concentrated. Purification bychromatography (silica gel, 1-4% methanol in dichloromethane) affordedthe title compound (0.008 g, 14%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s,1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.63 (s, 1H), 7.27 (s, 1H), 6.78 (t,J=9.00 Hz, 2H), 6.49-6.55 (m, 2H), 4.74 (s, 2H), 3.57 (s, 3H), 2.39 (s,3H). MS (ESI+) m/z 361 (M+H)⁺.

Example 124-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 12a 2,4-difluoro-N-(4-((methylsulfonyl)methyl)phenyl)aniline

A 100 mL microwave tube was charged with 2,4-difluoroaniline (1.235 mL,12.26 mmol), Example 9a (3.0539 g, 12.26 mmol), diacetoxypalladium(0.055 g, 0.245 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.234g, 0.490 mmol), cesium carbonate (5.59 g, 17.16 mmol), toluene (40.9 mL)and tert-butanol (8.17 mL). The tube was sealed, and the reactionmixture was heated in a Milestone Ethos microwave, 5 minute ramp to 150°C., then 10 minutes fixed hold time. The reaction mixture was filteredthrough a 10 g Celite SPE column and rinsed with ethyl acetate. Thefiltrate was concentrated, and the residue was purified by flashchromatography (20-100% ethyl acetate/heptanes) to provide the titlecompound (3.44 g, 94% yield).

Example 12b2-bromo-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline

A 500 mL round-bottomed flask was charged with Example 12a (3.4409 g,11.57 mmol) and acetic acid (116 mL). The reaction mixture was placedinto a water bath. N-bromosuccinimide (2.060 g, 11.57 mmol) was added in2 portions, 10 minutes apart. The reaction mixture was stirred atambient temperature for 1.5 hours. The reaction mixture was quenchedwith 200 mL 10% sodium thiosulfate and diluted with water. The reactionmixture was extracted 2× with ethyl acetate. The combined organic layerswere washed 2× with 2N NaOH (until the pH of the aqueous was >7) and 1×with saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was taken upinto ethyl acetate, then treated with heptanes. The resulting slurry wasstirred for 30 minutes and filtered to provide the title compound 3.82g, 88% yield).

Example 12c4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 250 mL round-bottomed flask was charged with Example 12b (1.9813 g,5.27 mmol), Example 1f (2.051 g, 4.79 mmol), sodium carbonate (1.776 g,16.76 mmol), tris(dibenzylideneacetone)dipalladium (II) (0.219 g, 0.239mmol), and 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane(0.238 g, 0.814 mmol). The solids were sparged with nitrogen for 30minutes. Degassed dioxane (38.3 mL) and water (9.58 mL) were added. Thereaction was heated at 60° C. for 3 hours. The reaction mixture wascooled to room temperature and partitioned between ethyl acetate andwater. The organic layer was washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate, filtered, andconcentrated. The residue was taken up into dichloromethane, trituratedwith ether, and filtered to provide the title compound (2.30 g, 80%yield).

Example 12d4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 20 mL microwave tube was charged with Example 12c (1.9830 g, 3.32mmol), lithium hydroxide monohydrate (1.392 g, 33.2 mmol), dioxane (16mL) and water (5.33 mL) to give a white suspension. The reaction mixturewas heated at 50° C. for 72 hours. The reaction mixture was cooled toambient temperature and diluted with water. The resulting suspension wasfiltered, and the solid was rinsed with water and dried under vacuumovernight (1.25 g, 85% yield).

Example 12e4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 5 mL microwave tube was charged with Example 12d (0.0504 g, 0.114mmol), paraformaldehyde (0.051 g, 0.568 mmol) and methanol (1.137 mL).4N HCl in dioxane (0.568 mL, 2.273 mmol) was added. The tube was closedand the reaction mixture was heated at 90° C. for 1 hour. The reactionmixture was cooled to room temperature and diluted with ether. Theresulting suspension was filtered, and the solid was rinsed with etherand collected. The solid and the filtrate were combined and purified byflash chromatography (0-5% methanol/dichloromethane) to provide thetitle compound (0.0234 g, 45% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 11.83(s, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.66 (s, 1H), 7.26 (d, J=10.2 Hz, 1H),6.99-7.19 (m, 3H), 6.81 (s, 1H), 4.72-4.78 (m, 2H), 4.49 (d, J=1.1 Hz,3H), 4.01 (m, 1H), 3.62 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 456.3(M+H)⁺.

Example 134-(cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 13a 2-bromo-N-(cyclopropylmethyl)aniline

A 100 mL flask was charged with 2-bromoaniline (1.72 g, 10.0 mmol),cyclopropanecarbaldehyde (0.374 mL, 5.00 mmol), acetic acid (2.86 mL,50.0 mmol) and dichloromethane (50 mL). The resulting solution washeated at 50° C. for 1 hour. The solution was cooled in an ice bath andthe sodium triacetoxyborohydride (2.119 g, 10.0 mmol) was addedportionwise over a few minutes. After 15 minutes, the ice bath wasremoved and the solution was stirred for 2 hours while warming toambient temperature. The reaction mixture was quenched with 2.5 M sodiumhydroxide (about 15 mL) and partitioned between saturated aqueous sodiumbicarbonate solution (100 mL) and ethyl acetate (100 mL). The layerswere separated and the organic layer was dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography (silica gel, 0-10% ethyl acetate in heptanes) to providethe title compound (1.05 g, 93%).

Example 13b4-(2-((cyclopropylmethyl)amino)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 25 mL vial was charged with Example 1f (244 mg, 0.570 mmol),tris(dibenzylideneacetone)dipalladium (0) (15.66 mg, 0.017 mmol),Example 13a (132.1 mg, 0.584 mmol),1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (18.33 mg,0.063 mmol) and potassium phosphate (363 mg, 1.710 mmol). This mixturewas sparged with argon for 30 minutes. To this vial was added a mixtureof dioxane (4 mL) and water (1 mL) [that had been degassed with argonfor 30 minutes]. The mixture was heated at 750 C for 2.5 hours. Uponcooling the reaction mixture was partitioned between ethyl acetate (75mL) and 50% saturated aqueous sodium chloride (100 mL). The layers wereseparated and the organic layer was treated with 3-mercaptopropylfunctionalized silica gel (Aldrich), dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography (silica gel, 0-3% methanol in dichloromethane) to providethe title compound (266 mg, 100%).

Example 13c4-(2-((cyclopropylmethyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 25 mL flask was charged with Example 13b (255 mg, 0.570 mmol),cetyltrimethylammonium bromide (10.38 mg, 0.028 mmol), potassiumhydroxide (615 mg, 10.96 mmol), dioxane (9 mL) and water (3 mL). Themixture was heated at 900 C for 2.5 hours. Upon cooling, the mixture wasneutralized with 1M aqueous hydrogen chloride solution and partitionedbetween ethyl acetate (80 mL) and 50% saturated aqueous sodium chloride(75 mL). The layers were separated and the aqueous layer was extractedwith ethyl acetate (2×40 mL). The combined organics were dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by flash chromatography (silica gel, 0-5% methanol indichloromethane) to provide the title compound (120 mg, 72%).

Example 13d4-(cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 5 mL microwave vial was charged with Example 13c (60 mg, 0.205 mmol),paraformaldehyde (92 mg, 1.023 mmol), methanol (2 mL) and hydrogenchloride (4M in dioxane, 1.023 mL, 4.09 mmol). The vial was sealed andthe reaction mixture was heated at 90° C. for 1 hour. Upon cooling, thereaction mixture was partitioned between 50% saturated bicarbonatesolution (100 mL) and ethyl acetate (75 mL). The layers were separatedand the aqueous layer was extracted with ethyl acetate (50 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by flashchromatography (silica gel, 0-5% methanol in dichloromethane) to providethe title compound (52 mg, 83%). 1H NMR (400 MHz, DMSO-d₆) δ 11.74 (s,1H), 7.63-7.67 (m, 1H), 7.59 (s, 1H), 7.10-7.25 (m, 4H), 4.19 (s, 2H),3.60 (s, 3H), 2.68 (d, J=6.41 Hz, 2H), 0.74-0.87 (m, 1H), 0.45-0.36 (m,2H), −0.07 (q, J=4.78 Hz, 2H)). MS (ESI+) m/z 306.0 (M+H)⁺.

Example 14 methyl3-(4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate

A stock solution of Example 6c (0.086 M in methanol, 455 μL, 0.040 mmol,1.0 equivalent), HCl (4.0 M in dioxane, 195 μL, 0.78 mmol, 20 eq), andmethyl 4-oxobutanoate (0.40 M in methanol, 243 μL, 0.19 mmol, 5equivalents) were combined and heated under microwave conditions at 90°C. for 99 minutes. The reaction mixture was concentrated and purified byreverse phase HPLC (C8 column, CH₃CN/water (0.1% ammonium acetate),5-100% gradient) to afford the title compound (5.1 mg, 27% yield). ¹HNMR (400 MHz, DMSO-d₆-D₂O) δ 7.70 (s, 1H), 7.52 (s, 1H), 7.22-7.33 (m,2H), 7.12 (s, 1H), 4.43 (bs, 1H), 3.63 (s, 2H), 3.55 (m, 4H), 2.89 (s,3H), 1.71 (m, 2H), 0.74 (s, 1H), 0.02-0.37 (m, 2H), −0.13 (s, 2H). MS(APCI) m/z 484.1 (M+H)⁺.

Example 154-(cyclopropylmethyl)-3-(2-methoxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A stock solution of Example 6c (0.086 M in methanol, 455 μL, 0.040 mmol,1.0 equivalent), HCl (4.0 M in dioxane, 195 μL, 0.78 mmol, 20 eq), and3-methoxypropanal (0.40 M in methanol, 243 μL, 0.19 mmol, 5 equivalents)were combined and heated under microwave conditions at 90° C. for 99minutes. The reaction mixture was concentrated and purified by reversephase HPLC (C8 column, CH₃CN/water (0.1% ammonium acetate), 5-100%gradient) to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ7.69 (bs, 1H), 7.51 (s, 1H), 7.19-7.32 (m, 2H), 7.10 (s, 1H), 4.42 (bs,2H), 3.63 (s, 3H), 2.74-2.93 (m, 5H), 1.77 (s, 2H), 1.08-1.43 (m, 1H),0.70-0.83 (m, 1H), 0.02-0.40 (m, 2H), −0.11 (s, 2H). MS (APCI) m/z 456.1(M+H)⁺.

Example 163-benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A stock solution of Example 5e (0.11 M in methanol, 417 μL, 0.045 mmol,1.0 equivalent), HCl (4.0 M in dioxane, 226 μL, 0.90 mmol, 20equivalents), and 2-phenylacetaldehyde (0.40 M in methanol, 189 μL,0.225 mmol, 5 equivalents) were aspirated from their respective sourcevials, mixed through a perfluoroalkoxy mixing tube (0.2 mm innerdiameter), and loaded into an injection loop. The reaction segment wasinjected into a flow reactor (Hastelloy coil, 0.75 mm inner diameter,1.8 mL internal volume) set at 100° C., and passed through the reactorat 180 μL per minute (10 minute residence time). Upon exiting thereactor, the reaction mixture was loaded directly into an injection loopand purified by reverse phase HPLC (C8, CH₃CN/water (0.1% ammoniumacetate), 5-100% gradient) to afford the title compound. (3.4 mg, 17%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.70 (d, J=2.0 Hz, 1H), 7.51 (s,1H), 7.27 (t, J=7.2 Hz, 2H), 7.21 (dd, J=8.3, 6.1 Hz, 1H), 7.10 (dd,J=10.1, 4.3 Hz, 3H), 6.78 (d, J=0.4 Hz, 1H), 6.72 (d, J=8.1 Hz, 1H),4.54 (t, J=7.2 Hz, 1H), 4.36 (bs, 2H), 3.64 (s, 3H), 2.91-3.01 (m, 2H),2.88 (s, 3H). MS (APCI) m/z 434.0 (M+H)⁺.

Example 17 methyl3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate

Example 17 was prepared according to the procedure used for thepreparation of Example 16, substituting methyl 4-oxobutanoate for2-phenylacetaldehyde to provide the title compound (8.7 mg, 45% yield).¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.68 (d, J=2.0 Hz, 1H), 7.49 (s, 1H),7.14 (dd, J=8.2, 1.8 Hz, 1H), 7.11 (s, 1H), 7.03 (d, J=8.0 Hz, 1H), 4.36(bs, 2H), 4.27 (t, J=6.8 Hz, 1H), 3.63 (s, 3H), 3.55 (s, 3H), 2.87 (s,3H), 2.26-2.46 (m, 2H), 1.75-1.97 (m, 2H). MS (APCI) m/z 430.0 (M+H)⁺.

Example 1810-methyl-7-((methylsulfonyl)methyl)-3-phenethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 18 was prepared according to the procedure used for thepreparation of Example 16, substituting 3-phenylpropanal for2-phenylacetaldehyde to provide the title compound (5.1 mg, 25% yield).¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.67 (d, J=2.0 Hz, 1H), 7.49 (s, 1H),7.21 (t, J=7.4 Hz, 2H), 7.01-7.19 (m, 6H), 4.36 (bs, 2H), 4.23-4.30 (m,1H), 3.63 (s, 3H), 2.86 (s, 3H), 2.72-2.84 (m, 1H), 2.58-2.71 (m, 1H),1.65-1.98 (m, 2H). MS (APCI) m/z 448.1 (M+H)⁺.

Example 193-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 19 was prepared according to the procedure used for thepreparation of Example 16, substituting 3-methylbutanal for2-phenylacetaldehyde to provide the title compound (4.4 mg, 24% yield).¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.67 (d, J=2.0 Hz, 1H), 7.48 (s, 1H),7.13 (dd, J=8.1, 2.0 Hz, 1H), 7.09 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 4.35(bs, 2H), 4.27 (t, J=7.0 Hz, 1H), 3.63 (s, 3H), 2.87 (s, 3H), 1.63-1.79(m, 1H), 1.54 (ddd, J=13.6, 7.7, 6.0 Hz, 1H), 1.33-1.48 (m, 1H), 0.89(t, J=6.6 Hz, 6H). MS (APCI) m/z 400.0 (M+H)⁺.

Example 20(E)-3-(4-fluorostyryl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 20 was prepared according to the procedure used for thepreparation of Example 16, substituting(E)-3-(4-fluorophenyl)acrylaldehyde for 2-phenylacetaldehyde to providethe title compound (4.8 mg, 23% yield). ¹H NMR (400 MHz, DMSO D₂O) δ7.67 (s, 1H), 7.52 (s, 1H), 7.31 (dd, J=8.7, 5.6 Hz, 2H), 7.11-7.17 (m,1H), 7.01-7.11 (m, 4H), 6.45 (d, J=15.8 Hz, 1H), 6.29 (dd, J=15.9, 6.9Hz, 1H), 5.00 (d, J=6.7 Hz, 1H), 4.35 (s, 2H), 3.65 (s, 3H), 2.82 (s,3H). MS (APCI) m/z 464.0 (M+H)⁺.

Example 217-amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(1H)-oneExample 21a

3-Bromo-2-chloro-5-nitropyridine (3.936 g, 16.58 mmol), 4-fluoroaniline(5.53 g, 49.7 mmol) and dimethyl sulfoxide (DMSO) (33.2 mL) werecombined and stirred at 120° C. for 1 hour. The reaction mixture wascooled to ambient temperature, producing a solid. Precipitation wasinduced further by the addition of 150 mL of water. The solid wascollected by filtration and rinsed with 600 mL of water. The solid waspurified by flash chromatography (silica gel, 0 to 20% ethyl acetate inheptanes) and then triturated with 15% ethyl acetate in heptanes toprovide 4.2 g (81%) of the title compound.

Example 21b4-(2-((4-fluorophenyl)amino)-5-nitropyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 21b was prepared according to the procedure used for thepreparation of Example 1j, substituting Example 21a for Example 1i, toprovide the title compound.

Example 21c4-(4-fluorophenyl)-10-methyl-7-nitro-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one

Example 21c was prepared according to the procedure used for thepreparation of Example 1k, substituting Example 21b for Example 1j, toprovide the title compound.

Example 21d7-amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 21c (0.06 g, 0.153 mmol), and Pd/C (0.033 g, 0.031mmol) in ethyl acetate (10 mL) was treated with a balloon of hydrogen.The reaction mixture was stirred overnight. The solvent was removed, andresidue was purified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA),0-100% gradient) to afford the title compound (0.0351 g, 63%) as the bisTFA salt. ¹H NMR (500 MHz, DMSO-d₆) δ 11.92 (s, 1H), 7.85 (d, J=2.44 Hz,1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.36 (d, J=2.44 Hz, 1H), 6.84 (t,J=8.85 Hz, 1H), 6.44-6.47 (m, 2H), 4.81 (s, 2H), 3.56 (s, 3H). MS (ESI+)m/z 362.1 (M+H)⁺.

Example 22N-(4-(4-fluorophenyl)-10-methyl-1-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide

A mixture of Example 21d (0.025 g, 0.069 mmol), ethanesulfonyl chloride(0.027 g, 0.208 mmol), and triethylamine (0.042 g, 0.415 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 2 hours.The solvent was removed, and residue was treated with dioxane (2 mL) and2.0 N NaOH (1 mL). The reaction mixture was heated at 850 C for 2 hours.The reaction mixture was partitioned between water and ethyl acetate.The organic layer was separated. The aqueous layer was neutralized topH=7, and extracted with additional ethyl acetate twice. The combinedorganic layers were washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by reverse phase HPLC (C18,CH₃CN/water (0.1% TFA), 0-100% gradient) to afford the title compound(0.022 g, 0.049 mmol, 70.1% yield) as mono TFA salt. ¹H NMR (500 MHz,DMSO-d₆) δ 11.89 (s, 1H), 10.12 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H),7.59 (s, 1H), 7.35 (s, 1H), 6.83 (t, J=8.39 Hz, 1H), 6.49-6.50 (m, 2H),4.76 (s, 2H), 3.57 (s, 3H), 3.27 (q, J=7.17 Hz, 2H), 1.29 (t, J=7.17 Hz,3H). MS (ESI+) m/z 451.1 (M+H)⁺.

Example 23N-(4-(2,4-difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamideExample 23a 3-bromo-N-(2,4-difluorophenyl)-5-nitropyridin-2-amine

A mixture of 3-bromo-2-chloro-5-nitropyridine (2.374 g, 10 mmol) and2,4-difluoroaniline (2.58 g, 20 mmol) in DMSO (20 mL) was heated at 100°C. for 2 hours. After cooling, the reaction mixture was partitionedbetween water and ethyl acetate. The organic layer was separated, andthe aqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography on silicagel, eluting with 1:20 ethyl acetate/heptans to give the title compound(1.75 g, 5.30 mmol, 53.0% yield) as yellow crystals.

Example 23b4-(2-((2,4-difluorophenyl)amino)-5-nitropyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of 3 Example 23a (0.330 g, 1 mmol), Example if (0.471 g, 1.100mmol), 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane(0.034 g, 0.117 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.027g, 0.030 mmol), and potassium phosphate (0.531 g, 2.500 mmol) in dioxane(4 mL) and water (1 mL) was degassed and back-filled with nitrogenseveral times. The reaction mixture was heated at 60° C. overnight. Tothis reaction mixture were added dioxane (5 mL) and 2.0 N NaOH (5 mL).The reaction was heated at 90° C. for 2 hours. After cooling, thereaction mixture was partitioned between 0.1 N HCl and ethyl acetate.The aqueous pH appeared around 5. The organic layer was separated, andthe aqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was triturated with 3:7 ethyl acetate/heptanesto give the title compound (0.365 g, 0.919 mmol, 92% yield).

Example 23c4-(2,4-difluorophenyl)-10-methyl-7-nitro-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 23b (0.17 g, 0.428 mmol), 4 N hydrogen chloride indioxane (3.21 mL, 12.84 mmol) and formaldehyde (0.128 g, 4.28 mmol) inmethanol (2) was heated at 130° C. under microwave conditions for 2hours. After cooling, the reaction mixture was partitioned between waterand ethyl acetate. The organic layer was separated, and the aqueouslayer was extracted with additional ethyl acetate three times. Thecombined organic layers were washed with saturated aqueous sodiumchloride solution, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was used for the next reaction withoutadditional purification.

Example 23d7-amino-4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one

A mixture of 23c (0.18 g, 0.440 mmol), iron (0.123 g, 2.199 mmol), andammonium hydrochloride (0.047 g, 0.879 mmol) in tetrahydrofuran (5 mL),water (1 mL) and ethanol (5 mL) was heated at 90° C. for 2 hours. Thesolid was filtered off, and washed with ethyl acetate several times. Itwas then poured into water. Organic layer was separated, and the aqueouslayer was extracted with ethyl acetate several times. The combinedorganic layers were washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA),0-100% gradient) to give 0.05 g (23.1%) of the title compound as a bisTFA salt.

Example 23eN-(4-(2,4-difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide

A mixture of Example 23d (0.05 g, 0.132 mmol), ethanesulfonyl chloride(0.017 g, 0.132 mmol), and triethylamine (0.013 g, 0.132 mmol) indichloromethane (5 mL) was stirred at ambient temperature for 2 hours.The solvent was removed, and residue was treated with dioxane (2 mL) and2.0 N NaOH (1 mL). The reaction mixture was heated at 850 C for 2 hours.The reaction mixture was partitioned between water and ethyl acetate.The organic layer was separated. The aqueous layer was neutralized topH=7, and extracted with additional ethyl acetate twice. The combinedorganic layers were washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by reverse phase HPLC (C18,CH₃CN/water (0.1% TFA), 0-100% gradient) to afford the title compound(0.048 g, 0.77 mmol, 58.3% yield) as mono TFA salt. ¹H NMR (500 MHz,DMSO-d₆) δ 11.92 (s, 1H), 9.76 (s, 1H), 7.91-7.93 (m, 2H), 7.62 (s, 1H),7.29-7.35 (m, 1H), 7.20 (d, J=2.75 Hz, 1H), 7.07-7.13 (m, 1H), 7.00-7.06(m, 1H), 4.76 (s, 2H), 3.65 (s, 3H), 3.14 (q, J=7.32 Hz, 2H), 1.25 (t,J=7.32 Hz, 3H). MS (ESI+) m/z 472.2 (M+H)⁺.

Example 244-butyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 5 mL vial was charged with Example 5f (75 mg, 0.218 mmol),butyraldehyde (0.039 mL, 0.437 mmol), acetic acid (0.125 mL, 2.184 mmol)and dichloromethane (2.5 mL). The vial was sealed and the mixture washeated at 60° C. for 1 hour. The reaction mixture was cooled in an icebath and sodium triacetoxyborohydride (93 mg, 0.437 mmol) was addedportionwise over a few minutes. Stirring was continued overnight whilewarming to ambient temperature. The reaction mixture was quenched with 1M sodium hydroxide (2 mL) and partitioned between saturated sodiumbicarbonate solution (50 mL) and ethyl acetate (50 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×25mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography (silica gel, 0-10% methanol in dichloromethane) toprovide the title compound (74 mg, 85%). ¹H NMR (400 MHz, DMSO-d₆) δ11.76 (s, 1H), 7.68 (d, J=1.83 Hz, 1H), 7.50 (s, 1H), 7.23-7.29 (m, 1H),7.17-7.21 (m, 1H), 7.14 (d, J=2.14 Hz, 1H), 4.44 (s, 2H), 4.08 (s, 2H),3.62 (s, 3H), 2.90-2.98 (m, 5H), 1.32-1.43 (m, 2H), 1.14-1.25 (m, 2H),0.77 (t, J=7.32 Hz, 3H). MS (ESI+) m/z 400.1 (M+H)⁺.

Example 25 tert-butyl3-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)pyrrolidine-1-carboxylate

Example 25 was prepared according to the procedure used for thepreparation of Example 24, substituting tert-butyl3-formylpyrrolidine-1-carboxylate for butyraldehyde to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 11.79 (d, J=2.14 Hz, 1H), 7.70 (d,J=1.83 Hz, 1H), 7.53 (s, 1H), 7.24-7.29 (m, 1H), 7.18-7.24 (m, 1H), 7.14(d, J=2.44 Hz, 1H), 4.44 (s, 2H), 4.12 (s, 2H), 3.62 (s, 3H), 3.13-3.24(m, 2H), 3.03-3.12 (m, 1H), 2.75-2.97 (m, 6H), 2.18-2.30 (m, 1H), 1.73(d, J=6.71 Hz, 1H), 1.26-1.49 (m, 10H). MS (ESI+) m/z 526.9 (M+H)⁺.

Example 2610-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 5 mL vial was charged with Example 5f (75 mg, 0.218 mmol),tetrahydrofuran-3-carbaldehyde (50% weight in water, 131 mg, 0.655mmol), acetic acid (0.125 mL, 2.184 mmol) and dichloromethane (2.5 mL).The vial was sealed and the mixture was heated at 60° C. for 1 hour. Thereaction mixture was cooled in an ice bath and sodiumtriacetoxyborohydride (93 mg, 0.437 mmol) was added portionwise overseveral minutes. Stirring was continued overnight while warming toambient temperature. The reaction mixture was quenched with 1 M sodiumhydroxide (2 mL) and partitioned between saturated sodium bicarbonatesolution (50 mL) and ethyl acetate (50 mL). The layers were separatedand the aqueous layer was extracted with ethyl acetate (2×25 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by flashchromatography (silica gel, 0-10% methanol in dichloromethane) toprovide the title compound (79.6 mg, 85%). ¹H NMR (400 MHz, DMSO-d₆) δ11.79 (s, 1H), 7.70 (d, J=1.83 Hz, 1H), 7.54 (s, 1H), 7.24-7.30 (m, 1H),7.18-7.23 (m, 1H), 7.15 (d, J=2.44 Hz, 1H), 4.45 (s, 2H), 4.13 (s, 2H),3.45-3.66 (m, H), 3.25-3.30 (m, 1H), 2.94 (s, 3H), 2.84-2.92 (m, 1H),2.77 (dd, J=12.36, 8.70 Hz, 1H), 2.20-2.35 (m, 1H), 1.65-1.85 (m, 1H),1.33-1.46 (m, 1H). MS (ESI+) m/z 428.1 (M+H)⁺.

Example 274-((4,4-difluorocyclohexyl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 27 was prepared according to the procedure used for thepreparation of Example 24, substituting4,4-difluorocyclohexanecarbaldehyde for butyraldehyde, to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 11.77 (d, J=1.83 Hz, 1H),7.69 (d, J=1.83 Hz, 1H), 7.51 (s, 1H), 7.24-7.29 (m, 1H), 7.19-7.23 (m,1H), 7.13 (d, J=2.44 Hz, 1H), 4.44 (s, 2H), 4.08 (s, 2H), 3.62 (s, 3H),2.94 (s, 3H), 2.82 (d, J=7.02 Hz, 2H), 1.82-1.96 (m, 2H), 1.48-1.76 (m,5H), 0.94-1.10 (m, 2H). MS (ESI+) m/z 428.1 (M+H)⁺.

Example 28 tert-butyl4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)piperidine-1-carboxylate

Example 28 was prepared according to the procedure used for thepreparation of Example 24, substituting tert-butyl4-formylpiperidine-1-carboxylate for butyraldehyde, to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 11.77 (d, J=2.44 Hz, 1H), 7.68 (d,J=1.83 Hz, 1H), 7.51 (s, 1H), 7.23-7.28 (m, 1H), 7.18-7.23 (m, 1H), 7.13(d, J=2.44 Hz, 1H), 4.44 (s, 2H), 4.08 (s, 2H), 3.81 (d, J=11.90 Hz,2H), 3.62 (s, 3H), 2.94 (s, 3H), 2.80 (d, J=6.10 Hz, 2H), 2.51 (s, 2H),1.56 (d, J=10.68 Hz, 3H), 1.34 (s, 9H), 0.76-0.92 (m, 2H). MS (ESI+) m/z540.9 (M+H)⁺.

Example 2910-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydro-2H-pyran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 29 was prepared according to the procedure used for thepreparation of Example 24, substitutingtetrahydro-2H-pyran-3-carbaldehyde for butyraldehyde, to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 11.77 (d, J=1.83 Hz, 1H),7.68 (d, J=2.14 Hz, 1H), 7.51 (s, 1H), 7.23-7.29 (m, 1H), 7.18-7.23 (m,1H), 7.15 (d, J=2.75 Hz, 1H), 4.44 (s, 2H), 4.00-4.13 (m, 2H), 3.56-3.70(m, 5H), 3.16-3.25 (m, 1H), 2.91-3.00 (m, 4H), 2.83-2.91 (m, 1H),2.73-2.81 (m, 1H), 1.57-1.72 (m, 2H), 1.28-1.50 (m, 2H), 1.07 (t, J=9.61Hz, 1H). MS (ESI+) m/z 540.9 (M+H)⁺.

Example 304-(4,4-difluorocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 30 was prepared according to the procedure used for thepreparation of Example 24, substituting 4,4-difluorocyclohexanone forbutyraldehyde, to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆)δ 11.84 (d, J=1.70 Hz, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.25 (s, 2H),7.19 (d, J=2.71 Hz, 1H), 4.46 (s, 2H), 4.08 (s, 2H), 3.62 (s, 3H), 2.94(s, 3H), 2.88 (s, 1H), 1.96 (d, J=12.55 Hz, 2H), 1.19-1.86 (m, 6H). MS(ESI+) m/z 462.1 (M+H)⁺.

Example 314-(4-fluorophenyl)-(3,3-²H₂)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 20 mL microwave tube was charged Example 9e (0.0506 g, 0.119 mmol),formaldehyde-d₂ (0.095 mL, 0.595 mmol) and methanol (1.189 mL). 4N HClin dioxane (0.595 mL, 2.379 mmol) was added. The tube was closed and thereaction was heated to 90° C. for 2 hours. The reaction was cooled toroom temperature. The reaction was partitioned between dichloromethaneand saturated aqueous sodium bicarbonate. The aqueous layer wasextracted with dichloromethane. The combined organic layers were washedwith saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was taken upinto dichloromethane and triturated with ether. The resulting slurry wasstirred for 10 minutes and filtered. The white solid was rinsed withether, collected, and dried in a 60° C. vacuum oven to provide the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 11.80-11.85 (m, 1H), 7.91 (d,J=2.0 Hz, 1H), 7.60 (s, 1H), 7.40-7.51 (m, 1H), 7.33 (d, J=4.5 Hz, 2H),6.72-6.85 (m, 2H), 6.36-6.46 (m, 2H), 4.53-4.59 (m, 2H), 3.56 (s, 3H),3.00 (s, 3H). MS (ESI+) m/z 440.1 (M+H)⁺.

Example 327-fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(1H)-oneExample 32a4-(2-amino-5-fluoropyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

3-Bromo-5-fluoropyridin-2-amine (0.3 g, 1.571 mmol), Example if (0.673g, 1.571 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.043 g,0.047 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.046 g,0.157 mmol) and potassium phosphate (1.167 g, 5.50 mmol) were combinedand sparged with argon for 15 minutes. Meanwhile a solution of 4:1dioxane/water (8 mL) was sparged with nitrogen for 15 minutes and thentransferred by syringe into the reaction vessel under argon. The mixturewas stirred for 2 hours at 60° C., cooled, diluted with 50 mL of waterand the crude solid was collected by filtration, washed with additionalwater and dried to afford the title compound (0.648 g, 100%).

Example 32b4-(5-fluoro-2-((4-fluorophenyl)amino)pyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

1-Bromo-4-fluorobenzene (0.424 g, 2.425 mmol), Example 32a (0.5 g, 1.212mmol), diacetoxypalladium (10.89 mg, 0.048 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.046g, 0.097 mmol) and cesium carbonate (0.790 g, 2.425 mmol) were combinedin a mixture of t-butanol (2.021 mL) and toluene (10.10 mL) and heatedby microwave at 150° C. for 2 hours. The mixture was cooled andpartitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, dried (anhydrous sodiumsulfate), treated with 3-mercaptopropyl functionalized silica, filteredand concentrated. Purification by chromatography (silica gel, 1-5%methanol in dichloromethane) afforded the title compound (0.065 g, 15%).

Example 32c7-fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(1H)-one

Example 32b (0.055 g, 0.156 mmol), paraformaldehyde (0.141 g, 4.68 mmol)and hydrogen chloride (4M in 1,4-dioxane, 1 mL, 4.00 mmol) were combinedin methanol (1 mL) in a sealed tube and heated by microwave at 130° C.for 2 hours, cooled and concentrated. Purification by reverse phase HPLC(C18, CH₃CN/water (0.1% TFA), 0-100% gradient) afforded the titlecompound as the TFA salt (0.009 g, 12%). ¹H NMR (500 MHz, DMSO-d₆) δ11.91 (s, 1H), 8.43 (d, J=2.75 Hz, 1H), 8.27 (dd, J=9.92, 2.90 Hz, 1H),7.85 (s, 1H), 7.36 (d, J=2.44 Hz, 1H), 6.78-6.92 (m, 2H), 6.43-6.53 (m,2H), 4.78 (s, 2H), 3.56 (s, 3H). MS (ESI+) m/z 365 (M+H)⁺.

Example 334-(4-fluorophenyl)-7,10-dimethyl-3-phenyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 11c and benzaldehyde (0.116 mL, 1.148 mmol) inacetic acid (1 mL) was heated in a sealed tube at 110° C. for 15 hours,cooled and concentrated. Purification by reverse phase HPLC (C18,CH₃CN/water (0.1% TFA), 0-100% gradient) afforded the title compound(0.016 g, 25%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 8.02 (s, 1H),7.99 (s, 1H), 7.68 (s, 1H), 7.38 (d, J=2.75 Hz, 1H), 6.98-7.12 (m, 5H),6.81-6.88 (m, 2H), 6.71-6.78 (m, 2H), 6.68 (s, 1H), 3.60 (s, 3H), 2.25(s, 3H). MS (ESI+) m/z 437 (M+H)⁺.

Example 34 ethyl4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate

Example 34 was prepared according to the procedure used for thepreparation of Example 7, substituting Example 9e for Example 6c toprovide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 11.95-12.00 (m,1H), 7.85 (d, J=2.0 Hz, 1H), 7.62 (s, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.24(d, J=8.1 Hz, 1H), 6.87 (t, J=8.7 Hz, 2H), 6.46-6.61 (m, 2H), 6.18-6.29(m, 1H), 4.44-4.62 (m, 2H), 3.70-4.03 (m, 2H), 3.58 (s, 3H), 2.93 (s,3H), 0.87-1.03 (m, 3H). MS (ESI+) m/z 510.1 (M+H)⁺.

Example 35 tert-butyl4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carbonyl)piperazine-1-carboxylateExample 35a4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylicacid

A 100 mL round-bottomed flask was charged with Example 34 (0.453 g,0.888 mmol), dioxane (6.66 mL) and water (2.22 mL) to give a yellowsolution. Lithium hydroxide hydrate (0.186 g, 4.44 mmol) was added. Thereaction mixture was stirred at ambient temperature for 5 hours. Thereaction mixture was quenched with 1N hydrochloric acid. The resultingslurry was stirred for 10 minutes and filtered. The solid was rinsedwith water, dried on the frit overnight and collected to provide thetitle compound (0.3664 g, 86% yield).

Example 35b tert-butyl4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carbonyl)piperazine-1-carboxylate

A 2 mL microwave tube was charged with Example 35a (0.0498 g, 0.103mmol), tert-butyl piperazine-1-carboxylate (0.019 g, 0.103 mmol),polymer supported-carbodiimide (0.248 g, 0.310 mmol),1H-benzo[d][1,2,3]triazol-1-ol (0.014 g, 0.103 mmol),N-ethyl-N-isopropylpropan-2-amine (0.036 mL, 0.207 mmol) anddimethylacetamide (1.034 mL). The tube was sealed, and the reactionmixture was heated in a Biotage Creator at 110° C. for 10 minutes fixedhold time. The reaction mixture was filtered, and the resin was rinsedthoroughly with ethyl acetate. The filtrate was washed twice withsaturated aqueous sodium chloride. The organic layer was dried overanhydrous magnesium sulfate, filtered and concentrated. The residue waspurified by flash chromatography (silica gel, 0-10% methanol indichloromethane) to provide the title compound (0.0133 g, 20% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 11.78-11.89 (m, 1H), 7.77-7.89 (m, 1H),7.50-7.61 (m, 1H), 7.35-7.45 (m, 1H), 7.20-7.34 (m, 2H), 6.76-6.90 (m,2H), 6.43-6.57 (m, 2H), 6.33-6.43 (m, 1H), 4.42-4.66 (m, 2H), 3.66-3.81(m, 2H), 3.40-3.61 (m, 5H), 2.98-3.22 (m, 2H), 2.92 (s, 3H), 2.66-2.85(m, 2H), 1.47-1.29 (m, 9H). MS (ESI+) m/z 549.8 (M+H)⁺.

Example 3610-methyl-7-((methylsulfonyl)methyl)-4-(pyrrolidin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 4 mL vial was charged with Example 25 (98 mg, 0.186 mmol) anddichloromethane (2 mL). The mixture was cooled in an ice bath and2,2,2-trifluoroacetic acid (1 mL, 12.98 mmol) was added. Stirring wascontinued for 2 hours as the reaction mixture warmed to ambienttemperature. The reaction mixture was concentrated under a heated streamof nitrogen and the residue was partitioned between saturated sodiumbicarbonate solution (50 mL) and ethyl acetate (50 mL). The layers wereseparated and the aqueous layer was extracted with 10% methanol indichloromethane (16×100 mL). The combined organics were also dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100%gradient) to afford the title compound (56.6 mg, 56%) as thetrifluoroacetic acid salt. ¹H NMR (400 MHz, PYRIDINE-d₅) δ 13.48 (s,1H), 11.08-11.34 (m, 1H), 8.06 (d, J=1.83 Hz, 1H), 7.56 (s, 2H),7.38-7.42 (m, 1H), 7.36 (d, J=8.24 Hz, 1H), 4.76 (s, 2H), 4.25-4.40 (m,2H), 3.63 (s, 3H), 3.58 (dd, J=11.29, 7.63 Hz, 1H), 3.42-3.52 (m, 1H),3.30-3.42 (m, 2H), 3.14-3.21 (m, 1H), 3.14 (s, 3H), 3.02 (dd, J=12.51,9.16 Hz, 1H), 2.59-2.72 (m, 1H), 1.90-2.04 (m, 1H), 1.59-1.73 (m, 1H).MS (ESI+) m/z 427.1 (M+H)⁺.

Example 3710-methyl-7-((methylsulfonyl)methyl)-4-(piperidin-4-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 4 mL vial was charged with Example 28 (81.5 mg, 0.151 mmol) anddichloromethane (2 mL). The mixture was cooled in an ice bath and2,2,2-trifluoroacetic acid (1 mL, 13 mmol) was added. Stirring wascontinued for 2 hours while warming to ambient temperature. The reactionmixture was concentrated under a heated stream of nitrogen and theresidue was purified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA),0-100% gradient) to afford the title compound (76.9 mg, 92%) as thetrifluoroacetic acid salt. ¹H NMR (400 MHz, PYRIDINE-d₅) δ 13.45 (d,J=1.53 Hz, 1H), 10.89 (d, 1H), 8.08 (d, J=2.14 Hz, 1H), 7.61 (dd,J=8.24, 1.83 Hz, 2H), 7.41 (d, J=2.44 Hz, 1H), 7.37 (d, J=7.93 Hz, 1H),4.77 (s, 2H), 4.27 (s, 2H), 3.64 (s, 3H), 3.52 (d, J=12.51 Hz, 2H), 3.13(s, 3H), 3.00 (d, J=6.41 Hz, 2H), 2.88-2.98 (m, 2H), 1.80-1.99 (m, 3H),1.55 (d, J=12.82 Hz, 2H). MS (ESI+) m/z 441.1 (M+H)⁺.

Example 387-fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-oneExample 38a4-(2-amino-5-fluoropyridin-3-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 38a was prepared according to the procedure used for thepreparation of Example 8a, substituting 3-bromo-5-fluoropyridin-2-aminefor 2-bromo-4-(methylsulfonyl)aniline and the reaction time was 4 hoursinstead of 3 hours, to provide the title compound in quantitative yield.

Example 38b4-(2-amino-5-fluoropyridin-3-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 38a (825 mg, 2.00 mmol), potassium hydroxide (1.68 g, 30.0 mmol)and cetyltrimethylammonium bromide (36.4 mg, 0.100 mmol) were combinedin a mixture of dioxane (20 mL) and water (10 mL). The reaction mixturewas heated at 100° C. for 3 hours and then cooled to ambienttemperature. To this mixture was added water, and the pH was adjusted topH 7 by the addition of 1M HCl. The mixture was extracted with ethylacetate and the organic layer was washed with saturated aqueous sodiumchloride twice, dried with anhydrous sodium sulfate, treated with3-mercaptopropyl functionalized silica gel, filtered, and concentrated.The residue was triturated with dichloromethane to afford the titlecompound (460 mg, 89%).

Example 38c7-fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one

A 5 mL vial was charged with Example 38b (25.8 mg, 0.100 mmol),paraformaldehyde (30 mg, 1.0 mmol) and methanol (2 mL). To thissuspension was added 4M HCl in dioxane (0.50 mL, 2.0 mmol). The vial wasclosed and heated in a microwave reactor at 120° C. for 2 hours. Thereaction mixture was cooled to ambient temperature and concentrated. Tothis residue was added water, and the pH was adjusted to pH 7 byaddition of saturated aqueous sodium bicarbonate. The residue wassonicated for 5 minutes and filtered to afford the title compound (23mg, 85%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.84 (s, 1H) 7.96-8.06 (m, 2H)7.79 (s, 1H) 7.18 (d, J=2.71 Hz, 1H) 6.16 (t, J=3.05 Hz, 1H) 4.15 (d,J=3.05 Hz, 2H) 3.61 (s, 3H). MS (ESI+) m/z 271 (M+H)⁺.

Example 39 ethyl7-fluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-3-carboxylate

A 5 mL vial was charged with Example 38b (25.8 mg, 0.100 mmol), 50%ethyl 2-oxoacetate in toluene (0.198 mL, 1.00 mmol) and ethanol (2 mL).To this suspension was added 4M HCl in dioxane (0.50 mL, 2.0 mmol). Thevial was closed and heated in a microwave reactor at 120° C. for 2hours. The reaction mixture was cooled to ambient temperature andconcentrated. The residue was purified by flash chromatography (silicagel, 2-4% methanol in dichloromethane) to afford the title compound (17mg, 50%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.10 (s, 1H) 7.96-8.06 (m, 2H)7.87 (s, 1H) 7.34 (d, J=2.71 Hz, 1H) 6.50 (d, J=5.43 Hz, 1H) 5.11 (d,J=5.43 Hz, 1H) 3.91 (q, J=7.12 Hz, 2H) 3.61 (s, 3H) 0.98 (t, J=7.12 Hz,3H). MS (ESI+) m/z 343 (M+H)⁺.

Example 404-(4-fluorophenyl)-3-(4-methoxypiperidine-1-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 40 was prepared according to the procedure used for thepreparation of Example 35b, substituting 4-methoxypiperidine fortert-butyl piperazine-1-carboxylate to provide the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ 11.78-11.83 (m, 1H), 7.81-7.86 (m, 1H), 7.55(s, 1H), 7.33-7.43 (m, 1H), 7.24-7.33 (m, 1H), 7.21 (d, J=7.7 Hz, 1H),6.79-6.89 (m, 2H), 6.43-6.53 (m, 2H), 6.28-6.40 (m, 1H), 4.46-4.61 (m,2H), 4.01 (d, J=1.1 Hz, 1H), 3.53-3.41 (m, 1H), 3.56 (s, 3H), 3.41-3.53(m, 1H), 3.25-3.29 (m, 5H), 2.92 (s, 3H), 1.89-2.14 (m, 1H), 1.69-1.89(m, 1H), 1.32-1.69 (m, 2H). MS (ESI+) m/z 579.0 (M+H)⁺

Example 414-(4-fluorophenyl)-10-methyl-3-(4-methylpiperazine-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 41 was prepared according to the procedure used for thepreparation of Example 35b, substituting 1-methylpiperazine fortert-butyl piperazine-1-carboxylate to provide the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ 11.79-11.85 (m, 1H), 7.84 (d, J=1.7 Hz, 1H),7.55 (s, 1H), 7.40 (dd, J=8.0, 1.9 Hz, 1H), 7.18-7.32 (m, 2H), 6.78-6.89(m, 2H), 6.45-6.54 (m, 2H), 6.32-6.40 (m, 1H), 4.47-4.61 (m, 2H),3.44-3.61 (m, 5H), 2.74-3.04 (m, 5H), 2.15-2.38 (m, 5H). MS (ESI+) m/z564.1 (M+H)⁺.

Example 425,7-difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 42a4-(2-amino-3,5-difluorophenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

2-Bromo-4,6-difluoroaniline (1.0 g, 4.81 mmol), Example if (2.059 g,4.81 mmol), tris(dibenzylideneacetone)dipalladium (0),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.141 g,0.481 mmol) and potassium phosphate (3.57 g, 16.83 mmol) were combinedand sparged with argon for 15 minutes. Meanwhile a solution of 4:1dioxane/water (8 mL) was sparged with nitrogen for 15 minutes andtransferred by syringe into the reaction vessel under argon. The mixturewas stirred for 2 hours at 60° C., cooled to ambient temperature, anddiluted with 100 mL of water. The resulting solid was collected byfiltration, washed with additional water and dried to afford the titlecompound (1.6 g, 77%).

Example 42b4-(2-amino-3,5-difluorophenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 42a (1.6 g, 3.73 mmol), potassium hydroxide (6.27 g, 112 mmol)and N,N,N-trimethylhexadecan-1-aminium bromide (0.068 g, 0.186 mmol)were combined in dioxane (33.1 mL)/water (16.6 mL) and heated at 100° C.for 3 hours, cooled, diluted with ethyl acetate and water and the pH wasadjusted to pH 8 by careful addition of 12 M HCl. The organic layer waswashed with saturated aqueous sodium chloride, dried (anhydrous sodiumsulfate), filtered and concentrated. Purification by chromatography(silica gel, 0.5-4% methanol in dichloromethane) afforded the titlecompound (0.80 g, 78%).

Example 42c5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 42b (0.25 g, 0.908 mmol) and paraformaldehyde(0.273 g, 9.08 mmol) in methanol (9.08 mL) was treated with hydrogenchloride (4M in 1,4-dioxane, 6.81 mL, 27.2 mmol). The mixture was heatedat 90° C. for 3 hours in a sealed tube, cooled and filtered to collect asolid that was rinsed repeatedly with diethyl ether. The solid wassonicated in 2 mL methanol and 20 mL 5% aqueous sodium bicarbonate for 5minutes and collected by filtration to afford the title compound (0.2 g,77%).

Example 42d5,7-difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of tetrahydrofuran-3-carboxaldehyde (0.131 g, 0.654 mmol) andExample 42c (0.063 g, 0.218 mmol) in dichloromethane (2.5 mL) in asealed tube was treated with acetic acid (0.125 mL, 2.180 mmol) andheated for 1 hour at 60° C., cooled to 0° C. and treated portionwisewith sodium triacetoxyhydroborate (0.092 g, 0.436 mmol). The reactionmixture was stirred for 18 hours allowing the mixture to warm to ambienttemperature. The mixture was partitioned between dichloromethane and 5%aqueous sodium bicarbonate. The organic layer was washed with saturatedaqueous sodium chloride, dried (anhydrous sodium sulfate) filtered andconcentrated. Purification by reverse phase HPLC (C18, CH₃CN/water (0.1%TFA), 0-100% gradient) afforded the title compound as a TFA salt (0.04g, 38%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.91 (s, 1H), 7.83 (d, J=2.03 Hz,1H), 7.41-7.46 (m, 1H), 7.06-7.22 (m, 2H), 4.19-4.30 (m, 1H), 4.00-4.10(m, 1H), 3.61 (s, 3H), 3.25-3.63 (m, 5H), 1.66-2.70 (m, 4H). MS (ESI+)m/z 372 (M+H)⁺.

Example 43 ethyl4-(4-fluorophenyl)-7,10-dimethyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-3-carboxylate

A mixture of ethyl glyoxylate (0.586 g, 2.87 mmol) and Example 11c (0.1g, 0.287 mmol) in ethanol (2 mL) was treated with hydrogen chloride (4Min 1,4-dioxane, 2.153 mL, 8.61 mmol). The mixture was heated at 120° C.for 18 hours in a sealed tube, cooled and concentrated. Purification byreverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100% gradient)afforded the title compound as a TFA salt (0.01 g, 6%). ¹H NMR (300 MHz,DMSO-d₆) δ 12.06 (d, J=1.70 Hz, 1H), 8.16 (s, 2H), 7.83 (s, 1H), 7.39(d, J=2.71 Hz, 1H), 6.92-7.00 (m, 2H), 6.74-6.81 (m, 2H), 6.18 (s, 1H),3.91 (d, J=7.12 Hz, 2H), 3.61 (s, 3H), 2.36 (s, 3H), 0.92 (t, J=7.12 Hz,3H). MS (ESI+) m/z 433 (M+H)⁺.

Example 44N-cyclopentyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

A 5 mL vial was charged with Example 5f (72.5 mg, 0.211 mmol),isocyanatocyclopentane (0.036 mL, 0.317 mmol),N-ethyl-N-isopropylpropan-2-amine (0.110 mL, 0.633 mmol),dichloromethane (2 mL) and N,N-dimethylformamide (2 mL). The reactionmixture was stirred for 18 hours at ambient temperature and then heatedat 90° C. for 72 hours. Upon cooling, the reaction mixture waspartitioned between 50% saturated aqueous sodium chloride (60 mL) anddichloromethane (60 mL). The layers were separated and the aqueous layerwas extracted with dichloromethane (2×50 mL). The combined extracts weredried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by flash chromatography (silica gel, 0-10% methanolin dichloromethane) to provide the title compound (59.1 mg, 62%). ¹H NMR(300 MHz, DMSO-d₆) δ 11.85 (d, J=2.37 Hz, 1H), 7.83 (d, J=2.03 Hz, 1H),7.63 (s, 1H), 7.33-7.40 (m, 1H), 7.25-7.31 (m, 1H), 7.20 (d, J=2.03 Hz,1H), 5.36 (d, J=15.94 Hz, 1H), 5.24 (d, J=6.78 Hz, 1H), 4.52-4.62 (m,1H), 4.40-4.51 (m, 1H), 3.96 (d, J=15.60 Hz, 1H), 3.69-3.83 (m, 1H),3.62 (s, 3H), 2.96 (s, 3H), 1.54-1.72 (m, 2H), 1.31-1.52 (m, 4H),1.09-1.27 (m, 2H). MS (ESI+) m/z 455.1 (M+H)⁺.

Example 45N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 45 was prepared according to the procedure used for thepreparation of Example 44, substituting isocyanatoethane forisocyanatocyclopentane to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 11.85 (d, J=1.36 Hz, 1H), 7.83 (d, J=1.70 Hz, 1H), 7.62 (s,1H), 7.34-7.40 (m, 1H), 7.26-7.32 (m, 1H), 7.19 (d, J=2.37 Hz, 1H), 5.59(s, 1H), 5.35 (d, J=15.94 Hz, 1H), 4.42-4.62 (m, 2H), 3.94 (d, J=15.60Hz, 1H), 3.59-3.66 (m, 3H), 2.97 (s, 3H), 2.75-2.96 (m, 2H), 0.85 (t,J=7.12 Hz, 3H). MS (ESI+) m/z 415.1 (M+H)⁺.

Example 46N-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 46 was prepared according to the procedure used for thepreparation of Example 44, substituting 1-fluoro-4-isocyanatobenzene forisocyanatocyclopentane to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 11.91 (d, J=2.37 Hz, 1H), 7.87 (s, 2H), 7.66 (s, 1H), 7.38(s, 2H), 7.28-7.34 (m, 2H), 7.25 (d, J=2.37 Hz, 1H), 6.95-7.02 (m, 2H),5.52 (d, J=15.60 Hz, 1H), 4.45-4.63 (m, 2H), 4.07 (d, J=16.62 Hz, 1H),3.63 (s, 3H), 2.98 (s, 3H). MS (ESI+) m/z 481.1 (M+H)⁺.

Example 474-butyl-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of butyraldehyde (0.079 g, 1.097 mmol) and Example 42c (0.063g, 0.219 mmol) in dichloroethane (1.0 mL) in a sealed tube was treatedwith acetic acid (0.126 mL, 2.193 mmol) and heated for 2 hours at 60°C., cooled to 0° C. and treated portionwise with sodiumtriacetoxyhydroborate (0.139 g, 0.658 mmol). The reaction mixture wasstirred for 18 hours allowing the mixture to warm to ambienttemperature. The mixture was partitioned between ethyl acetate and 5%aqueous sodium bicarbonate. The organic layer was washed with saturatedaqueous sodium chloride, dried (anhydrous sodium sulfate) filtered andconcentrated. Purification by chromatography (silica gel, 0.5-3%methanol in dichloromethane) gave a solid that was then triturated in9:1 hexane/ethyl acetate to afford the title compound (0.057 g, 76%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.81 (s, 1H), 7.40-7.45 (m, 1H),7.19 (d, J=2.14 Hz, 1H), 7.05-7.14 (m, 1H), 4.19-4.24 (m, 2H), 4.01-4.06(m, 2H), 3.61 (s, 3H), 1.13-1.33 (m, 4H), 0.76 (t, J=7.02 Hz, 3H). MS(ESI+) m/z 344 (M+H)⁺.

Example 485,7-difluoro-10-methyl-4-propyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of propionaldehyde (0.064 g, 1.097 mmol) and Example 42c(0.063 g, 0.219 mmol) in 1,2-dichloroethane (1.0 mL) in a sealed tubewas treated with acetic acid (0.126 mL, 2.193 mmol) and stirred for 2hours at 60° C., cooled to 0° C. and treated portion-wise with sodiumtriacetoxyhydroborate (0.139 g, 0.658 mmol). The reaction mixture wasstirred for 18 hours allowing the mixture to warm to ambienttemperature. The mixture was partitioned between ethyl acetate and 5%aqueous sodium bicarbonate. The organic layer was washed with saturatedaqueous sodium chloride solution, dried (anhydrous Na₂SO₄) filtered andconcentrated. Purification by flash chromatography (silica gel, 0.5-3%methanol in dichloromethane) gave a solid that was triturated in 9:1hexane/ethyl acetate to afford the title compound (0.044 g, 60%). ¹H NMR(400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.81 (s, 1H), 7.43 (d, J=10.68 Hz,1H), 7.18 (s, 1H), 7.05-7.13 (m, 1H), 4.17-4.25 (m, 1H), 3.99-4.08 (m,1H), 3.61 (s, 3H), 2.39-2.64 (m, 2H), 1.07-1.43 (m, 2H), 0.74 (t, J=7.32Hz, 3H). MS (ESI+) m/z 330 (M+H)⁺.

Example 494-(cyclopropylmethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 49 was prepared according to the procedure used for thepreparation of Example 47, substituting cyclopropanecarboxaldehyde forbutyraldehyde, to afford the title compound (0.054 g, 72%). ¹H NMR (500MHz, DMSO-d₆) δ 11.90 (s, 1H), 7.80 (s, 1H), 7.38-7.45 (m, 1H), 7.18 (d,J=1.83 Hz, 1H), 7.08-7.13 (m, 1H), 4.35 (d, J=15.87 Hz, 1H), 4.08 (d,J=15.87 Hz, 1H), 3.60 (s, 3H), 2.61 (dd, J=12.51, 6.41 Hz, 1H), 2.25(dd, J=12.51, 7.02 Hz, 1H), 0.73-0.82 (m, 1H), 0.23-0.36 (m, 1H),0.10-0.20 (m, 1H), −0.18-−0.08 (m, 1H), −0.42-−0.30 (m, 1H). MS (ESI+)m/z 342 (M+H)⁺.

Example 50 methyl4-(5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)butanoate

Example 50 was prepared according to the procedure used for thepreparation of Example 47, substituting 4-oxobutanoic acid methyl esterfor butyraldehyde, to afford the title compound (0.064 g, 74%). ¹H NMR(400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 7.82 (s, 1H), 7.43 (d, J=9.77 Hz,1H), 7.19 (s, 1H), 7.07-7.14 (m, 1H), 4.17-4.23 (m, 1H), 4.01-4.07 (m,1H), 3.61 (s, 3H), 3.52 (s, 3H), 2.59-2.68 (m, 2H), 2.30 (t, J=7.32 Hz,2H), 1.46-1.56 (m, 2H). MS (ESI+) m/z 388 (M+H)⁺.

Example 515,7-difluoro-10-methyl-4-(3-phenylpropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 51 was prepared according to the procedure used for thepreparation of Example 47, substituting 3-phenylpropionaldehyde forbutyraldehyde, to afford the title compound (0.062 g, 69%). ¹H NMR (400MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.81 (s, 1H), 7.43 (dd, J=10.83, 1.37 Hz,1H), 7.01-7.24 (m, 7H), 4.22-4.27 (m, 1H), 4.04-4.10 (m, 1H), 3.61 (s,3H), 2.49-2.69 (m, 4H), 1.44-1.67 (m, 2H). MS (ESI+) m/z 406 (M+H)⁺.

Example 5210-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(o-tolyl)-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

A 4 mL vial was charged with Example 5f (25 mg, 0.073 mmol),1-isocyanato-2-methylbenzene (13.39 mg, 0.091 mmol),diisopropylethylamine (38.4 L, 0.220 mmol) and N,N-dimethylformamide (1mL). The reaction mixture was heated at 80° C. for 18 hours. Thereaction mixture was concentrated and the residue was purified byreverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100% gradient) toafford the title compound (5.6 mg, 16%). ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ7.90 (d, J=1.8 Hz, 1H), 7.67 (s, 1H), 7.45-7.53 (m, 2H), 7.31-7.39 (m,1H), 7.26 (s, 1H), 7.02 (t, J=7.2 Hz, 2H), 6.86-6.94 (m, 1H), 5.40-5.48(m, 1H), 4.51-4.56 (m, 2H), 4.10-4.19 (m, 1H), 3.64 (s, 3H), 2.96 (s,3H), 1.76 (s, 3H). MS (ESI+) m/z 477.1 (M+H)⁺.

Example 53 2-ethylhexyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

A 4 mL vial was charged with Example 5f (15 mg, 0.044 mmol),2-ethylhexyl carbonochloridate (10.10 mg, 0.05 mmol),diisopropylethylamine (50 μL, 0.287 mmol) and N,N-dimethylacetamide (2mL). The reaction mixture was heated at 80° C. for 18 hours. To thismixture was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (19.93 mg, 0.05 mmol) and heating was continued for18 hours. The reaction mixture was concentrated and the residue waspurified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100%gradient) to afford the title compound (4.4 mg, 20.2%). ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.78-7.81 (m, 1H), 7.59-7.60 (m, 1H), 7.35-7.39 (m, 1H),7.27-7.31 (m, 1H), 7.20-7.22 (m, 1H), 5.17-5.23 (m, 1H), 4.44-4.54 (m,1H), 4.12-4.19 (m, 1H), 3.77 (bs, 2H), 3.61-3.64 (m, 3H), 2.90-2.94 (m,3H), 1.21-1.35 (m, 1H), 0.95-1.18 (m, 9H), 0.65-0.79 (m, 6H). MS (ESI+)m/z 500.1 (M+H)⁺.

Example 544-isobutyryl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 4 mL vial was charged with Example 5f (15 mg, 0.044 mmol), isobutyrylchloride (4.65 mg, 0.044 mmol), diisopropylethylamine (50 μL, 0.287mmol) and N,N-dimethylacetamide (2 mL). The reaction mixture was heatedat 80° C. for 18 hours. To this mixture was addedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (19.93 mg, 0.05 mmol) and heating was continued for18 hours. The reaction mixture was concentrated and the residue waspurified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100%gradient) to afford the title compound (1.3 mg, 7.2%).

¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.83-7.87 (m, 1H), 7.65-7.69 (m, 1H),7.42-7.45 (m, 1H), 7.33-7.41 (m, 1H), 7.20-7.26 (m, 1H), 5.45-5.60 (m,1H), 4.47-4.58 (m, 2H), 3.89-4.01 (m, 1H), 3.63 (s, 3H), 2.95 (s, 4H),1.96 (s, 1H), 0.91-1.01 (m, 3H), 0.44-0.55 (m, 2H). MS (ESI+) m/z 414.1(M+H)⁺.

Example 555,7-difluoro-10-methyl-4-phenethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1H)-one

Example 55 was prepared according to the procedure used for thepreparation of Example 47, substituting 2-phenylacetaldehyde forbutyraldehyde. Purification by reverse phase HPLC (C18, CH₃CN/water(0.1% TFA), 0-100% gradient) afforded the title compound (0.034 g, 40%).¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (d, J=1.22 Hz, 1H), 7.82 (s, 1H), 7.44(dd, J=10.38, 2.14 Hz, 1H), 7.08-7.21 (m, 5H), 7.02 (d, J=6.71 Hz, 2H),4.28-4.33 (m, 1H), 4.05-4.10 (m, 1H), 3.60 (s, 3H), 2.67-2.78 (m, 2H),2.45-2.53 (m, 2H). MS (ESI+) m/z 392 (M+H)⁺.

Example 564-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 56 was prepared according to the procedure used for thepreparation of Example 47, substituting2-(benzo[d][1,3]dioxol-5-yl)acetaldehyde for butyraldehyde. Purificationby reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100% gradient)afforded an impure product that was purified a second time (silica gel,0.5-3% methanol in dichloromethane) to give the title compound (0.033 g,32%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H), 7.80 (s, 1H), 7.43 (dd,J=8.70, 2.59 Hz, 1H), 7.19 (d, J=2.14 Hz, 1H), 7.08-7.16 (m, 1H), 6.68(d, J=7.93 Hz, 1H), 6.60 (s, 1H), 6.39-6.49 (m, 1H), 5.89 (s, 2H), 4.28(d, J=15.87 Hz, 1H), 4.05 (d, J=15.87 Hz, 1H), 3.60 (s, 3H), 2.33-2.88(m, 4H). MS (ESI+) m/z 436 (M+H)⁺.

Example 574-((1Z,3E)-2,4-diphenylbuta-1,3-dien-1-yl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 57 was prepared according to the procedure used for thepreparation of Example 47, substituting 2-phenylacetaldehyde forbutyraldehyde. The crude material was triturated in 1 mL of 50/50DMSO/methanol and filtered to collect a yellow solid (0.013 g, 12%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.62 (s, 1H), 7.60 (s, 1H), 6.95-7.16 (m,10H), 6.87 (d, J=15.87 Hz, 1H), 6.67 (dd, J=6.56, 2.59 Hz, 2H), 6.59 (s,1H), 6.50-6.56 (m, 1H), 5.42 (d, J=15.56 Hz, 1H), 4.68 (d, J=15.56 Hz,1H), 4.26 (d, J=14.95 Hz, 1H), 3.66 (s, 3H). MS (ESI+) m/z 492 (M+H)⁺.

Example 584-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamideExample 58a (Z)-ethyl3-(5-bromo-2-methoxy-3-nitropyridin-4-yl)-2-hydroxyacrylate

To a solution of ethanol (15 mL) and ether (150 mL) was added5-bromo-2-methoxy-4-methyl-3-nitropyridine (14.82 g, 60 mmol), diethyloxalate (13.15 g, 90 mmol), and potassium ethoxide (6.06 g, 72 mmol).The reaction mixture was heated at 45° C. for 24 hours. During thereaction, the flask was shaken by hand several times. After cooling, thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was extracted with additional ethyl acetate three times.The combined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography on silicagel eluting with 10-20% ethyl acetate in hexanes to 9.5 g of the titlecompound (yield 46%).

Example 58b ethyl4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 58a (9.5 g, 27.4 mmol) and iron powder (7.64 g, 137mmol) in ethanol (60 mL) and acetic acid (60 mL) was heated at 100° C.for 1 hour. The solid was filtered off, and then washed with additionalethyl acetate. The solvents were removed under reduced pressure to 20%of original volume, and the mixture was partitioned between water andethyl acetate. The aqueous layer was extracted with additional ethylacetate several times. The combined organic layers were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography on silica gel eluting with 20-40% ethyl acetate inhexanes to give 6.05 g of the title compound.

Example 58c ethyl1-benzyl-4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 58b (0.88 g, 2.94 mmol) in dimethylformamide (15 mL) was treatedwith 60% sodium hydride (0.106 g, 4.41 mmol, 0.117 g of a 60% in oildispersion). The solution was stirred at ambient temperature for 10minutes. To this solution was added benzyl bromide (0.59 g, 3.45 mmol).The reaction mixture was stirred for another 2 hours and was thenpartitioned between water and ethyl acetate. The aqueous layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography on silica gel eluting with 20-40% ethylacetate in hexanes to give 1.07 g of the title compound.

Example 58d ethyl1-benzyl-4-bromo-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

The mixture of Example 58c (2, 5.14 mmol) in dioxane (20 mL) was treatedwith 4.0 M HCl in dioxane (20 mL, 80 mmol). The reaction mixture wasstirred at 45° C. for 18 hours.

The mixture was concentrated to remove dioxane. The residue was slurryin petroleum ether to obtain the title compound (1.8 g, 4.80 mmol, 93%yield) as gray solid.

Example 58e

ethyl1-benzyl-4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

To a suspension of Example 58d (5.16 g, 13.75 mmol) in dimethylformamide(100 mL) at ambient temperature was added NaH (0.660 g, 16.50 mmol) andthe mixture was stirred at ambient temperature for 30 minutes.Iodomethane (1.032 mL, 16.50 mmol) was added into the reaction mixture.The reaction mixture was stirred at ambient temperature for 2 hours, andwas then partitioned between water and ethyl acetate. The aqueous layerwas extracted with additional ethyl acetate twice. The combined organiclayers were washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by chromatography on silica gel eluting with 20-40% ethylacetate in hexanes to give the title compound (4.23 g, 8.91 mmol, 64.8%yield).

Example 58f ethyl1-benzyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 58e (2 g, 5.14 mmol), bis(pinacolato)diboron (2.61g, 10.3 mmol), potassium acetate (1.11 g, 11.3 mmoltris(dibenzylideneacetone)dipalladium(0) (0.235 g, 0.257 mmol) and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.245 g, 0.514mmol) in dioxane (50 mL) was stirred at 90° C. for 16 hour under anargon atmosphere. The mixture was filtered through Celite, washed withethyl acetate several times and concentrated. The residue was purifiedby flash chromatography (silica gel, 50-75% ethyl acetate/petroleumether gradient) to afford the title compound (1.15 g, 40% yield).

Example 58g 2-bromo-4-((methylsulfonyl)methyl)aniline

To a solution of Example 5b (2 g, 10.80 mmol) in DMF (60 mL) was added1-bromopyrrolidine-2,5-dione (1.922 g, 10.80 mmol) and the reactionmixture was stirred at 15° C. for 1 hour. The reaction mixture wasquenched with 150 mL 10% sodium thiosulfate and 100 mL saturated sodiumbicarbonate. The reaction mixture was extracted with ethyl acetate threetimes. The combined organic layers were washed with saturated aqueoussodium chloride and concentrated to a semi-solid. Water was added, andthe resulting suspension was stirred at ambient temperature for 10minutes. The solid was collected by filtration and dried on the fritovernight to give the title compound (2.1 g, 7.85 mmol, 72.7% yield) asa tan solid.

Example 58h 2-bromo-N-(4-chlorophenyl)-4-((methylsulfonyl)methyl)aniline

To a 500 mL flask were added Example 58g (10 g, 37.9 mmol),1-chloro-4-iodobenzene (18.06 g, 76 mmol), PdOAc₂ (0.425 g, 1.893 mmol),xantphos (1.75 g, 3.03 mmol), Cs₂CO₃ (24.67 g, 76 mmol) and anhydrousdioxane (350 mL) under argon at ambient temperature. The mixture washeated at 110° C. for 18 hours. The reaction mixture was filteredthrough Celite and washed with ethyl acetate (100 mL). The filtrate wasconcentrated to remove the solvent and the residue was treated withethyl acetate (50 mL) and petroleum ether (20 mL) and the mixture wasstirred at ambient temperature for 15 min. The resulting solid wascollected by filtration, washed with a little petroleum ether and driedunder reduced pressure to give the title compound (9.6 g, 24.85 mmol,65.6% yield) as yellow solid.

Example 58i ethyl1-benzyl-4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 58i was prepared according to the procedure used for thepreparation of Example 5d, substituting Example 58h for Example 5c, andExample 58f for Example if, respectively, to provide the title compound.

Example 58j ethyl4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 58i (0.5 g, 0.828 mmol), anisole (0.181 mL, 1.655mmol) and H₂SO₄ (0.5 mL, 9.38 mmol) in TFA (20 mL, 260 mmol) was heatedat 90° C. for 10 hours. Excess TFA was removed under reduced pressure,and the residue was partitioned between water (10 mL) and ethyl acetate(20 mL). The organic layer was separated, and the aqueous layer wasextracted with additional ethyl acetate twice (20 mL). The combinedorganic layers were washed with saturated aqueous sodium bicarbonate (10mL), followed by saturated aqueous sodium chloride (10 mL), dried overanhydrous magnesium sulfate, filtered, and concentrated to give thetitle compound (0.38 g, 0.355 mmol, 42.9% yield) as pale solid.

Example 58k ethyl4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate

A mixture of Example 58j (0.200 g, 0.389 mmol), HCl (4 M in dioxane) (4mL, 16.00 mmol) and paraformaldehyde (0.234 g, 7.78 mmol) in methanol (2mL) was heated at 130° C. for 1.5 hours under microwave. The solvent wasremoved and the residue was partitioned between water and ethyl acetate.The aqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated to give the title compound (0.14 g, 0.130 mmol, 33.5%yield).

Example 5814-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylicacid

A mixture of Example 58k and LiOH (0.646 mL, 1.293 mmol) in dioxane (3mL) was heated at 65° C. for 18 hours. The solvent was removed and water(20 mL) was added. The aqueous layer was adjusted pH to 3 with 1N HCl.The solid was filtered and dried to give the title compound (0.25 g,0.487 mmol, 75% yield) as pale solid.

Example 58m4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

To a solution of Example 581 (0.1 g, 0.201 mmol) in anhydrousdichloromethane (5 mL) were added oxalyl chloride (0.035 mL, 0.402 mmol)and DMF (0.777 μL, 10.04 μmol) and the reaction mixture was stirred atambient temperature for 2 hours. The reaction mixture was concentratedto dryness. The residue was redissolved in dichloromethane (5 mL) andwas treated with ammonium hydroxide (25% wt/wt in water) (2 mL, 92 mmol)and the reaction mixture was stirred at ambient temperature overnight.The resulting solid was filtered and treated with methanol twice andfiltered again to provide the title compound (30 mg, 0.057 mmol, 28.3%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 12.23 (s, 1H), 7.93 (s, 1H), 7.83(s, 1H), 7.68 (s, 2H), 7.47 (d, J=7.4 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H),7.00 (d, J=8.4 Hz, 2H), 6.35 (d, J=8.6 Hz, 2H), 5.89 (m, 1H), 4.68-4.35(m, 3H), 3.59 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 497.1 (M+H)⁺

Example 594-(4-chlorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 59 was prepared according to the procedure used for thepreparation of Example 58m, substituting ethylamine for ammoniumhydroxide (25% wt/wt in water), to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆-MeOD): δ 8.33 (t, J=5.0 Hz, 1H), 7.93 (d, J=1.6 Hz,1H), 7.67 (s, 1H), 7.47 (dd, J=8.1, 1.8 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H),6.99 (d, J=9.1 Hz, 2H), 6.36 (d, J=9.1 Hz, 2H), 6.13-5.82 (m, 2H), 4.50(dd, J=56.8, 24.0 Hz, 3H), 3.58 (s, 3H), 3.01 (s, 3H), 1.25-1.14 (m,3H). MS (ESI+) m/z 525.0 (M+H)⁺

Example 604-(4-chlorophenyl)-10-methyl-2-(4-methylpiperazine-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 60 was prepared according to the procedure used for thepreparation of Example 58m, substituting 1-methylpiperazine for ammoniumhydroxide (25% wt/wt in water), to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆): δ 12.34 (s, 1H), 7.91 (d, J=1.7 Hz, 1H), 7.66 (s,1H), 7.47 (dd, J=8.1, 1.8 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.97 (d,J=9.1 Hz, 2H), 6.45 (d, J=9.1 Hz, 2H), 5.10 (d, J=16.8 Hz, 1H),4.68-4.40 (m, 3H), 3.69-3.40 (m, 7H), 3.00 (s, 3H), 2.36 (s, 4H), 2.21(s, 3H). MS (ESI+) m/z 580.2 (M+H)⁺

Example 61N-(2,6-dimethylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 61 was prepared according to the procedure used for thepreparation of Example 52, substituting 2-isocyanato-1,3-dimethylbenzenefor 1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.85 (s, 1H), 7.62 (s, 1H), 7.44 (s, 2H), 7.23(s, 1H), 6.86-6.96 (m, 3H), 5.31-5.40 (m, 1H), 4.48-4.53 (m, 2H),4.11-4.21 (m, 1H), 3.65 (s, 3H), 2.95 (s, 3H), 1.82 (s, 6H). MS (ESI+)m/z 491.1 (M+H)⁺.

Example 62N-(4-methoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 62 was prepared according to the procedure used for thepreparation of Example 52, substituting 1-isocyanato-4-methoxybenzenefor 1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.86 (d, J=1.9 Hz, 1H), 7.63 (s, 1H), 7.43 (dd,J=8.0, 1.9 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.25 (s, 1H), 7.08-7.15 (m,1H), 6.70-6.76 (m, 1H), 5.43-5.54 (m, 1H), 4.52 (bs, 2H), 4.02-4.16 (m,1H), 3.65 (d, J=10.2 Hz, 2H), 2.97 (s, 3H). MS (ESI+) m/z 493.0 (M+H)⁺.

Example 63N-(4-ethylphenethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 63 was prepared according to the procedure used for thepreparation of Example 52, substituting1-ethyl-4-(2-isocyanatoethyl)benzene for 1-isocyanato-2-methylbenzene toprovide the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.81 (d,J=2.0 Hz, 1H), 7.58 (s, 1H), 7.34 (dd, J=8.1, 2.0 Hz, 1H), 7.16-7.20 (m,2H), 7.00 (d, J=8.1 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H), 5.27-5.41 (m, 1H),4.49 (s, 2H), 3.93-4.01 (m, 1H), 3.64 (s, 3H), 3.02-3.20 (m, 2H), 2.95(s, 3H), 2.53-2.58 (m, 2H), 1.16 (t, J=7.6 Hz, 3H). MS (ESI+) m/z 519.1(M+H)⁺.

Example 6410-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-propyl-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 64 was prepared according to the procedure used for thepreparation of Example 52, substituting 1-isocyanatopropane for1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR (400MHz, DMSO-d₆/D₂O) δ 7.82 (d, J=1.9 Hz, 1H), 7.59 (s, 1H), 7.40 (dd,J=8.1, 2.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 5.33 (s, 1H),4.50 (s, 2H), 3.94-4.05 (m, 1H), 3.63 (s, 3H), 2.95 (s, 3H), 2.71-2.92(m, 2H), 1.25 (h, J=7.3 Hz, 2H), 0.66 (t, J=7.4 Hz, 3H). MS (ESI+) m/z429.1 (M+H)⁺.

Example 65N-(3-methoxybenzyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 65 was prepared according to the procedure used for thepreparation of Example 52, substituting1-(isocyanatomethyl)-3-methoxybenzene for 1-isocyanato-2-methylbenzeneto provide the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.82 (d,J=1.9 Hz, 1H), 7.59 (s, 1H), 7.40 (dd, J=8.1, 2.0 Hz, 1H), 7.30 (d,J=8.0 Hz, 1H), 7.19 (s, 1H), 5.33 (s, 1H), 4.50 (s, 2H), 3.94-4.05 (m,1H), 3.63 (s, 3H), 2.95 (s, 3H), 2.71-2.92 (m, 2H), 1.25 (h, J=7.3 Hz,2H), 0.66 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 507.0 (M+H)⁺.

Example 66N-(2-chloroethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 66 was prepared according to the procedure used for thepreparation of Example 52, substituting 1-chloro-2-isocyanatoethane for1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR (400MHz, DMSO-d₆/D₂O) δ 7.95 (d, J=0.4 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J=1.6Hz, 1H), 7.20 (dd, J=8.2, 1.9 Hz, 1H), 7.04 (d, J=8.1 Hz, 1H), 4.37 (s,2H), 4.13 (s, 2H), 3.79 (t, J=6.1 Hz, 2H), 3.73 (s, 3H), 3.69 (dt,J=6.4, 3.5 Hz, 2H), 2.89 (s, 3H). MS (ESI+) m/z 449.2 (M+H)⁺.

Example 67N-(cyclohexylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 67 was prepared according to the procedure used for thepreparation of Example 52, substituting (isocyanatomethyl)cyclohexanefor 1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.83 (d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.40 (dd,J=8.0, 2.0 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.19 (s, 1H), 5.24-5.37 (m,1H), 4.50 (s, 1H), 3.96-4.08 (m, 1H), 3.63 (s, 3H), 2.95 (s, 3H),2.65-2.83 (m, 1H), 1.45-1.58 (m, 3H), 1.34 (dd, J=13.7, 1.1 Hz, 1H),1.09-1.27 (m, 1H), 0.95-1.10 (m, 3H), 0.56-0.70 (m, 2H). MS (ESI+) m/z483.1 (M+H)⁺.

Example 68N-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 68 was prepared according to the procedure used for thepreparation of Example 52, substituting 2,4-difluoro-1-isocyanatobenzenefor 1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR(500 MHz, DMSO-d₆) δ 11.90-11.98 (m, 1H), 7.90 (bs, 1H), 7.70 (s, 1H),7.33-7.52 (m, 4H), 7.26 (d, J=1.0 Hz, 1H), 7.11-7.21 (m, 1H), 6.88-6.97(m, 1H), 5.46 (d, J=15.6 Hz, 1H), 4.60 (d, J=13.5 Hz, 1H), 4.50 (d,J=13.5 Hz, 1H), 4.10 (d, J=15.1 Hz, 1H), 3.64 (s, 3H), 2.98 (s, 3H). MS(ESI+) m/z 499.1 (M+H)⁺.

Example 69N-(4-isopropylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 69 was prepared according to the procedure used for thepreparation of Example 52, substituting 1-isocyanato-4-isopropylbenzenefor 1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.86 (d, J=1.8 Hz, 1H), 7.63 (s, 1H), 7.43 (dd,J=8.1, 2.0 Hz, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.25 (s, 1H), 7.12 (d, J=8.6Hz, 2H), 7.01 (d, J=8.5 Hz, 2H), 5.43-5.57 (m, 1H), 4.52 (s, 2H),4.04-4.14 (m, 1H), 3.64 (s, 3H), 2.97 (s, 3H), 2.77 (dt, J=14.1, 7.0 Hz,1H), 1.17-1.20 (m, 1H), 1.13 (d, J=6.9 Hz, 6H). MS (ESI+) m/z 505.2(M+H)⁺.

Example 70N-(2,6-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 70 was prepared according to the procedure used for thepreparation of Example 52, substituting 1,3-difluoro-2-isocyanatobenzenefor 1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.85 (d, J=1.7 Hz, 1H), 7.64 (s, 1H), 7.40-7.45(m, 2H), 7.15-7.25 (m, 2H), 6.94 (t, J=8.0 Hz, 2H), 5.45 (d, J=15.2 Hz,1H), 4.50 (d, J=4.0 Hz, 2H), 4.08-4.16 (m, 1H), 3.66 (s, 3H), 2.95 (s,3H). MS (ESI+) m/z 499.1 (M+H)⁺.

Example 71N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 71 was prepared according to the procedure used for thepreparation of Example 52, substituting1-fluoro-4-isocyanato-2-(trifluoromethyl)benzene for1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR (400MHz, DMSO-d₆/D₂O) δ 7.87 (d, J=1.7 Hz, 1H), 7.73 (dd, J=6.5, 2.7 Hz,1H), 7.64 (s, 1H), 7.58 (ddd, J=8.9, 5.6, 2.4 Hz, 1H), 7.43 (dd, J=8.1,1.8 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.25 (s, 1H), 7.21 (d, J=9.6 Hz,1H), 5.49-5.56 (m, 1H), 4.53 (d, J=3.5 Hz, 2H), 4.08-4.14 (m, 1H), 3.64(s, 3H), 2.97 (s, 3H). MS (ESI+) m/z 549.0 (M+H)⁺.

Example 72 ethyl4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4-carboxamido)methyl)cyclohexanecarboxylate

Example 72 was prepared according to the procedure used for thepreparation of Example 52, substituting ethyl4-(isocyanatomethyl)cyclohexanecarboxylate for1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR (400MHz, DMSO-d₆/D₂O) δ 7.83 (d, J=1.9 Hz, 1H), 7.59 (s, 1H), 7.41 (dd,J=8.1, 2.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 5.26-5.36 (m,1H), 4.50 (d, J=1.2 Hz, 2H), 3.95-4.08 (m, 3H), 3.63 (s, 3H), 2.95 (s,3H), 2.68-2.83 (m, 2H), 2.03 (tt, J=12.2, 3.7 Hz, 1H), 1.75 (dd, J=12.8,2.2 Hz, 2H), 1.36-1.46 (m, 2H), 1.06-1.19 (m, 6H), 0.60-0.71 (m, 2H). MS(ESI+) m/z 555.1 (M+H)⁺.

Example 73N-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide

Example 73 was prepared according to the procedure used for thepreparation of Example 52, substituting 1-isocyanato-3-methoxypropanefor 1-isocyanato-2-methylbenzene to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.83 (d, J=1.9 Hz, 1H), 7.60 (s, 1H), 7.41 (dd,J=8.1, 2.0 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.19 (s, 1H), 5.29-5.38 (m,1H), 4.50 (d, J=2.0 Hz, 2H), 3.94-4.04 (m, 1H), 3.63 (s, 3H), 3.15 (t,J=5.9 Hz, 2H), 3.06 (s, 3H), 2.98-3.04 (m, 1H), 2.95 (s, 3H), 2.86-2.93(m, 1H), 1.47 (p, J=6.4 Hz, 2H). MS (ESI+) m/z 555.1 (M+H)⁺.

Example 7410-methyl-7-((methylsulfonyl)methyl)-4-tosyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 4 mL vial was charged with Example 5f (15 mg, 0.04 mmol),4-methylbenzene-1-sulfonyl chloride (19 mg, 0.1 mmol),diisopropylethylamine (15 μL, 0.08 mmol) and N,N-dimethylacetamide (0.75mL). The reaction mixture was heated at 50° C. for 18 hours. Thereaction mixture was concentrated and the residue was purified byreverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100% gradient) toafford the title compound (1.4 mg, 6%). ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ7.66 (d, J=1.83 Hz, 1H), 7.47-7.49 (m, 1H), 7.41 (dd, J=8.24, 1.83 Hz,1H), 7.25 (s, 1H), 7.22 (s, 1H), 6.77-6.80 (m, 2H), 6.72-6.75 (m, 2H),5.21 (d, J=16.48 Hz, 1H), 4.58-4.62 (m, 1H), 4.52 (d, J=4.88 Hz, 1H),4.49 (s, 1H), 3.51 (s, 3H), 2.98 (s, 3H), 2.15 (s, 3H). MS (APCI+) m/z498 (M+H)⁺.

Example 754-([1,1′-biphenyl]-4-ylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 75 was prepared according to the procedure used for thepreparation of Example 74, substituting biphenyl-4-sulfonyl chloride for4-methylbenzene-1-sulfonyl chloride to provide the title compound. ¹HNMR (500 MHz, DMSO-d₆/D₂O) δ 7.66 (d, J=2.14 Hz, 1H) 7.52-7.55 (m, 3H)7.48 (t, J=7.32 Hz, 2H) 7.42-7.45 (m, 2H) 7.29 (s, 1H) 7.20-7.23 (m, 3H)6.93 (d, J=8.54 Hz, 2H) 5.29 (d, J=16.48 Hz, 1H) 4.48-4.63 (m, 3H) 3.18(s, 3H) 2.98 (s, 3H). MS (APCI+) m/z 560 (M+H)⁺.

Example 764-((4-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 76 was prepared according to the procedure used for thepreparation of Example 74, substituting 4-methoxybenzene-1-sulfonylchloride for 4-methylbenzene-1-sulfonyl chloride to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ 7.65 (d, J=2.14 Hz, 1H)7.47-7.50 (m, 1H) 7.39-7.43 (m, 1H) 7.24 (s, 2H) 6.78 (d, J=9.16 Hz, 2H)6.44 (d, J=8.85 Hz, 2H) 5.21 (d, J=16.48 Hz, 1H) 4.57-4.62 (m, 1H) 4.50(s, 1H) 4.46-4.48 (m, J=2.75 Hz, 1H) 3.69 (s, 3H) 3.49 (s, 3H) 2.97 (s,3H). MS (APCI+) m/z 514 (M+H)⁺.

Example 7710-methyl-7-((methylsulfonyl)methyl)-4-(phenylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 77 was prepared according to the procedure used for thepreparation of Example 74, substituting benzenesulfonyl chloride for4-methylbenzene-1-sulfonyl chloride to provide the title compound. ¹HNMR (500 MHz, DMSO-d₆/D₂O) δ 7.65 (d, J=1.83 Hz, 1H) 7.47-7.51 (m, 1H)7.41 (dd, J=8.09, 1.98 Hz, 1H) 7.22-7.26 (m, 2H) 7.21 (s, 1H) 6.93-6.98(m, 2H) 6.88-6.91 (m, 2H) 5.24 (d, J=16.48 Hz, 1H) 4.58-4.62 (m, 1H)4.48-4.54 (m, 2H) 3.47 (s, 3H) 2.97 (s, 3H). MS (APCI+) m/z 484 (M+H)⁺.

Example 784-((2-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 78 was prepared according to the procedure used for thepreparation of Example 74, substituting 2-methoxybenzene-1-sulfonylchloride for 4-methylbenzene-1-sulfonyl chloride to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ 7.74 (d, J=1.83 Hz, 1H) 7.50(s, 1H) 7.33-7.39 (m, 1H) 7.26-7.30 (m, 2H) 7.12-7.16 (m, 2H) 6.81 (d,J=8.24 Hz, 1H) 6.72 (t, J=7.48 Hz, 1H) 5.25 (d, J=16.48 Hz, 1H)4.54-4.59 (m, 1H) 4.41-4.52 (m, 2H) 3.58 (s, 3H) 3.44 (s, 3H) 2.99 (s,3H). MS (APCI+) m/z 514 (M+H)⁺.

Example 7910-methyl-7-((methylsulfonyl)methyl)-4-((4-phenoxyphenyl)sulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 79 was prepared according to the procedure used for thepreparation of Example 74, substituting 4-phenoxybenzene-1-sulfonylchloride for 4-methylbenzene-1-sulfonyl chloride to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ 7.70 (d, J=1.83 Hz, 1H)7.47-7.52 (m, 3H) 7.41 (dd, J=8.24, 1.83 Hz, 1H) 7.38 (s, 1H) 7.28 (t,J=7.48 Hz, 1H) 7.21 (s, 1H) 7.08 (d, J=7.63 Hz, 2H) 6.91-6.94 (m, 2H)6.39-6.44 (m, 2H) 5.22 (d, J=16.48 Hz, 1H) 4.58-4.63 (m, 1H) 4.47-4.56(m, 2H) 3.57 (s, 3H) 2.98 (s, 3H). MS (APCI+) m/z 576 (M+H)⁺.

Example 804-((4-fluorophenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 80 was prepared according to the procedure used for thepreparation of Example 74, substituting 4-fluorobenzene-1-sulfonylchloride for 4-methylbenzene-1-sulfonyl chloride to provide the titlecompound. ¹H NMR (500 MHz, DMSO-d₆/D₂O) δ 7.67 (d, J=1.83 Hz, 1H)7.48-7.51 (m, 1H) 7.42 (dd, J=8.09, 1.68 Hz, 1H) 7.29 (s, 1H) 7.25 (s,1H) 6.96 (dd, J=8.85, 5.19 Hz, 2H) 6.76 (t, J=8.85 Hz, 2H) 5.23 (d,J=16.48 Hz, 1H) 4.57-4.63 (m, 1H) 4.47-4.56 (m, 2H) 3.51 (s, 3H) 2.98(s, 3H). MS (APCI+) m/z 502 (M+H)⁺.

Example 814-(2-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 81 was prepared according to the procedure used for thepreparation of Example 54, substituting 2-naphthoyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.96-7.99 (m, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.80 (d,J=7.02 Hz, 1H), 7.71-7.76 (m, 1H), 7.63-7.67 (m, 2H), 7.57-7.61 (m, 1H),7.46-7.53 (m, 2H), 7.42 (s, 1H), 7.08 (dd, J=8.39, 1.37 Hz, 1H), 5.93(d, J=14.95 Hz, 1H), 4.39-4.45 (m, 1H), 4.31-4.38 (m, 1H), 4.20 (d,J=14.65 Hz, 1H), 3.73 (s, 3H), 2.77 (s, 3H). MS (ESI+) m/z 498.1 (M+H)⁺.

Example 82 methyl3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate

Example 12d (44.3 mg, 0.100 mmol) and methyl 4-oxobutanoate (58.1 mg,0.500 mmol) were combined in tetrahydrofuran (1 mL). To this suspensionwas added 1M titanium(IV) chloride in dichloromethane (0.200 mL, 0.200mmol). The reaction mixture was stirred at ambient temperature for 20hours, and partitioned with ethyl acetate and water. The organic layerwas washed with saturated aqueous sodium chloride, dried with anhydroussodium sulfate, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 2-4% methanol in dichloromethane) toafford the title compound (38 mg, 70%). ¹H NMR (300 MHz, DMSO-d₆) δ11.91 (d, J=2.14 Hz, 1H) 7.85 (d, J=1.83 Hz, 1H) 7.69 (s, 1H) 7.24 (dd,J=8.24, 1.83 Hz, 1H) 7.04-7.13 (m, 2H) 6.81-7.02 (m, 3H) 5.03 (t, J=7.63Hz, 1H) 4.38-4.63 (m, 2H) 3.64 (s, 3H) 3.55 (s, 3H) 2.93 (s, 3H)2.35-2.46 (m, 2H) 1.82-2.03 (m, 1H) 1.34-1.61 (m, 1H). MS (ESI+) m/z 542(M+H)⁺.

Example 834-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentaazadibenzo[cd,f]azulen-11(1H)-oneExample 83a 5-chloro-N-(2,4-difluorophenyl)pyrimidin-4-amine

A mixture of 2,4-difluoroaniline (0.433 g, 3.36 mmol),4,5-dichloropyrimidine (0.5 g, 3.36 mmol), cesium carbonate (2.187 g,6.71 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)(0.097 g, 0.168 mmol) and diacetoxypalladium (0.038 g, 0.168 mmol) werecombined in toluene (4 mL), sealed, sparged for 15 minutes with argonand heated at 110° C. for 18 hours. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed withsaturated aqueous sodium chloride, dried (anhydrous sodium sulfate),treated with 3-mercaptopropyl functionalized silica, filtered andconcentrated. Purification by chromatography (silica gel, 10-50% ethylacetate in heptanes) afforded the title compound (0.66 g, 81%).

Example 83b4-(4-((2,4-difluorophenyl)amino)pyrimidin-5-yl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 83a (0.2 g, 0.828 mmol), Example if (0.355 g, 0.828 mmol),tris(dibenzylideneacetone)dipalladium (0) (0.038 g, 0.041 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.041 g,0.141 mmol) and sodium carbonate (0.307 g, 2.90 mmol) were combined andsparged with argon for 15 minutes. Meanwhile a solution of 4:1dioxane/water (4 mL) was sparged with nitrogen for 15 minutes andtransferred by syringe into the reaction vessel under argon. The mixturewas stirred for 18 hour at 80° C., cooled, diluted with 100 mL ethylacetate and 20 mL of water and filtered through Celite to removeelemental palladium. The filtrate layers were separated. The organiclayer was washed with saturated aqueous sodium chloride, dried(anhydrous sodium sulfate), treated with 3-mercaptopropyl functionalizedsilica gel, filtered and concentrated. Purification by chromatography(silica gel, 0.5-4% methanol in dichloromethane) afforded the titlecompound (0.272 g, 65%).

Example 83c4-(4-((2,4-difluorophenyl)amino)pyrimidin-5-yl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 83b (0.26 g, 0.512 mmol) and lithium hydroxide monohydrate(0.215 g, 5.12 mmol) were combined in dioxane (4 mL) and water (1.333mL) and heated at 50° C. for 18 hours. The mixture was cooled, dilutedwith water and the pH was adjusted to pH 9 with 1 M HCl. The resultingsolid was collected by filtration, rinsed with water and dried toconstant mass affording the title compound (0.171 g, 94%).

Example 83d4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentaazadibenzo[cd,f]azulen-11(1H)-one

Example 83c (0.03 g, 0.085 mmol) and paraformaldehyde (0.025 g, 0.849mmol) were combined in methanol (1.0 mL) and treated with hydrogenchloride (4M in 1,4-dioxane, 1.0 mL, 4.00 mmol). The mixture was sealedand heated at 130° C. for 2 hours by microwave. The mixture was cooled,diluted with ether and filtered to collect the HCl salt of the titlecompound (0.0025 g, 7%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.75 (d, J=2.44Hz, 1H), 10.45 (s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 7.77 (d, J=2.75 Hz,1H), 7.40-7.52 (m, 3H), 7.17 (t, J=8.39 Hz, 1H), 5.58 (d, J=14.95 Hz,1H), 4.81 (d, J=15.26 Hz, 1H), 3.58 (s, 3H). MS (ESI+) m/z 366 (M+H)⁺.

Example 84 (R)-ethyl4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate

Example 34 (13.4 mg, 0.026 mmol) was subjected to SFC purification usinga modified Berger Instruments PrepSFC™ system. A manual version of theBerger system was integrated with a Gilson 232 autosampler for sampleinjection and a Cavro MiniPrep™ pipettor customized for fractioncollection at atmospheric pressure (Olson, J.; Pan, J.; Hochlowski, J.;Searle, P.; Blanchard, D. JALA 2002, 7, 69-74). Custom designedcollection shoes allowed collection into 18×150 mm tubes and a methanolwash system allows washing of shoes between fractions to maximizerecovery and avoid cross-contamination of fractions. The system wascontrolled using SFC ProNTo™ software (version 1.5.305.15) and an Abbottdeveloped Visual Basic application for autosampler and fractioncollector control. The outlet pressure was 100 bar, oven temperature at35° C., and mobile phase flow rate at 40 mL/min on a ChiralPak OD-Hcolumn (21×250 mm, 5 micron). Samples were injected as solutions in 1.5mL methanol. The preparative SFC system was controlled using SFC ProNTo™software (version 1.5.305.15) and custom software for autosampler andfraction collector control. Fractions were collected based upon UVsignal threshold and on-line Thermo MSQ mass spectrometry was used formolecular mass confirmation, using ESI ionization in positive mode. Massspectra were acquired using a Navigator4.0 software and an Abbottdeveloped Visual Basic interface to communicate with SFC controllingsoftware to provide two white solids (Example 84, 6.5 mg, 48% yield, andExample 85 (6.0 mg, 44% yield). The first eluting enantiomer wasarbitrarily assigned as the R-isomer (Example 84), and the secondeluting enantiomer as the S-isomer (Example 85). ¹H NMR (300 MHz,DMSO-d₆) δ 11.95-12.00 (m, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.62 (s, 1H),7.37 (d, J=1.9 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 6.87 (t, J=8.7 Hz, 2H),6.46-6.61 (m, 2H), 6.18-6.29 (m, 1H), 4.44-4.62 (m, 2H), 3.70-4.03 (m,2H), 3.58 (s, 3H), 2.93 (s, 3H), 0.87-1.03 (m, 3H). MS (ESI+) m/z 510.1(M+H)⁺.

Example 85 (S)-ethyl4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate

¹H NMR (300 MHz, DMSO-d₆) δ 11.95-12.00 (m, 1H), 7.85 (d, J=2.0 Hz, 1H),7.62 (s, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 6.87 (t,J=8.7 Hz, 2H), 6.46-6.61 (m, 2H), 6.18-6.29 (m, 1H), 4.44-4.62 (m, 2H),3.70-4.03 (m, 2H), 3.58 (s, 3H), 2.93 (s, 3H), 0.87-1.03 (m, 3H). MS(ESI+) m/z 510.1 (M+H)⁺.

Example 86 2-methoxyethyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 86 was prepared according to the procedure used for thepreparation of Example 53, substituting 2-methoxyethyl carbonochloridatefor 2-ethylhexyl carbonochloridate to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.78-7.80 (m, 1H), 7.61 (s, 1H), 7.35-7.39 (m,1H), 7.33 (s, 1H), 7.23 (s, 1H), 5.20-5.30 (m, 1H), 4.49 (d, J=6.8 Hz,2H), 3.88-4.20 (m, 2H), 3.63 (s, 3H), 3.33-3.39 (m, 1H), 3.12 (s, 2H),2.94 (s, 3H). MS (ESI+) m/z 446.0 (M+H)⁺.

Example 87 ethyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 87 was prepared according to the procedure used for thepreparation of Example 53, substituting ethyl carbonochloridate for2-ethylhexyl carbonochloridate to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.78-7.80 (m, 1H), 7.61 (s, 1H), 7.35-7.39 (m,1H), 7.32 (s, 1H), 7.23 (s, 1H), 5.21-5.27 (m, 1H), 4.49 (d, J=6.8 Hz,2H), 4.12-4.17 (m, 1H), 3.85-3.99 (m, 2H), 3.63 (s, 3H), 2.95 (s, 3H),1.00-1.08 (m, 3H). MS (ESI+) m/z 416.1 (M+H)⁺.

Example 88 pentyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 88 was prepared according to the procedure used for thepreparation of Example 53, substituting pentyl carbonochloridate for2-ethylhexyl carbonochloridate to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.79 (d, J=1.9 Hz, 1H), 7.60 (s, 1H), 7.37 (dd,J=8.1, 1.9 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.22 (s, 1H), 5.22 (d,J=15.5 Hz, 1H), 4.44-4.54 (m, 2H), 4.14 (d, J=15.6 Hz, 1H), 3.91 (dd,J=11.9, 5.4 Hz, 1H), 3.80-3.87 (m, 1H), 3.63 (s, 3H), 2.94 (s, 3H),1.33-1.41 (m, 2H), 1.03-1.18 (m, 4H), 0.75 (t, J=7.1 Hz, 3H). MS (ESI+)m/z 458.1 (M+H)⁺.

Example 89 4-chlorobutyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 89 was prepared according to the procedure used for thepreparation of Example 53, substituting 4-chlorobutyl carbonochloridatefor 2-ethylhexyl carbonochloridate to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.80 (d, J=1.9 Hz, 1H), 7.61 (s, 1H), 7.36-7.39(m, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.23 (s, 1H), 5.23 (d, J=15.7 Hz, 1H),4.45-4.54 (m, 2H), 4.15 (d, J=15.8 Hz, 1H), 3.93-3.99 (m, 1H), 3.83-3.92(m, 1H), 3.63 (s, 3H), 3.40-3.47 (m, 2H), 2.94 (s, 3H), 1.47-1.58 (m,4H). MS (ESI+) m/z 478.0 (M+H)⁺.

Example 90 naphthalen-2-yl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 90 was prepared according to the procedure used for thepreparation of Example 53, substituting naphthalen-2-ylcarbonochloridate for 2-ethylhexyl carbonochloridate to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.76-7.88 (m, 4H), 7.71(s, 1H), 7.55-7.63 (m, 1H), 7.39-7.50 (m, 4H), 7.29-7.33 (m, 1H), 7.07(d, J=8.9 Hz, 1H), 5.33-5.46 (m, 1H), 4.46-4.57 (m, 2H), 4.27-4.38 (m,1H), 3.67 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 513.9 (M+H)⁺.

Example 91 p-tolyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 91 was prepared according to the procedure used for thepreparation of Example 53, substituting p-tolyl carbonochloridate for2-ethylhexyl carbonochloridate to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.84 (d, J=1.9 Hz, 1H), 7.68 (s, 1H), 7.47-7.54(m, 1H), 7.42 (dd, J=8.0, 1.8 Hz, 1H), 7.29 (s, 1H), 7.08 (d, J=8.2 Hz,2H), 6.77 (d, J=8.5 Hz, 2H), 5.30-5.37 (m, 1H), 4.46-4.56 (m, 2H),4.22-4.32 (m, 1H), 3.66 (s, 3H), 2.95 (s, 3H), 2.23 (s, 3H). MS (ESI+)m/z 478.2 (M+H)⁺.

Example 92 neopentyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 92 was prepared according to the procedure used for thepreparation of Example 53, substituting neopentyl carbonochloridate for2-ethylhexyl carbonochloridate to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.81 (d, J=1.8 Hz, 1H), 7.62 (s, 1H), 7.38 (dd,J=8.1, 1.9 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.23 (s, 1H), 5.23 (d,J=15.5 Hz, 1H), 4.44-4.54 (m, 2H), 4.18 (d, J=15.6 Hz, 1H), 3.63 (s,3H), 3.27-3.29 (m, 2H), 2.91 (s, 3H), 0.62-0.79 (m, 9H). MS (ESI+) m/z458.1 (M+H)⁺.

Example 93 phenyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 93 was prepared according to the procedure used for thepreparation of Example 53, substituting phenyl carbonochloridate for2-ethylhexyl carbonochloridate to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.85 (d, J=1.9 Hz, 1H), 7.69 (s, 1H), 7.50-7.55(m, 1H), 7.42 (dd, J=8.0, 2.0 Hz, 1H), 7.29 (t, J=7.8 Hz, 3H), 7.14 (t,J=7.3 Hz, 1H), 6.89 (dd, J=8.6, 1.1 Hz, 2H), 5.30-5.39 (m, 1H),4.46-4.57 (m, 2H), 4.26-4.34 (m, 1H), 3.66 (s, 3H), 2.95 (s, 3H). MS(ESI+) m/z 464.1 (M+H)⁺.

Example 94 4-fluorophenyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 94 was prepared according to the procedure used for thepreparation of Example 53, substituting 4-fluorophenyl carbonochloridatefor 2-ethylhexyl carbonochloridate to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.85 (d, J=1.7 Hz, 1H), 7.68 (s, 1H), 7.50-7.57(m, 1H), 7.42 (dd, J=8.2, 2.0 Hz, 1H), 7.29 (s, 1H), 7.07 (t, J=8.8 Hz,2H), 6.91-6.96 (m, 2H), 5.31-5.38 (m, 1H), 4.46-4.56 (m, 2H), 4.25-4.34(m, 1H), 3.66 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 482.0 (M+H)⁺.

Example 95 2-methoxyphenyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 95 was prepared according to the procedure used for thepreparation of Example 53, substituting 2-methoxyphenylcarbonochloridate for 2-ethylhexyl carbonochloridate to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.84 (d, J=1.8 Hz, 1H),7.68 (s, 1H), 7.49-7.55 (m, 1H), 7.41 (dd, J=8.2, 1.9 Hz, 1H), 7.27 (s,1H), 7.08-7.14 (m, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.83-6.86 (m, 2H),5.29-5.36 (m, 1H), 4.45-4.56 (m, 2H), 4.23-4.33 (m, 1H), 3.67 (s, 3H),3.54 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 494.1 (M+H)⁺.

Example 96 2-fluoroethyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 96 was prepared according to the procedure used for thepreparation of Example 53, substituting 2-fluoroethyl carbonochloridatefor 2-ethylhexyl carbonochloridate to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.80 (d, J=1.5 Hz, 1H), 7.62 (s, 1H), 7.38 (dd,J=8.3, 1.7 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.24 (d, J=0.6 Hz, 1H), 5.27(d, J=15.6 Hz, 1H), 4.45-4.55 (m, 3H), 4.34-4.39 (m, 1H), 3.99-4.28 (m,3H), 3.63 (s, 3H), 2.94 (s, 3H). MS (ESI+) m/z 434.0 (M+H)⁺.

Example 97 4-methoxyphenyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 97 was prepared according to the procedure used for thepreparation of Example 53, substituting 4-methoxyphenylcarbonochloridate for 2-ethylhexyl carbonochloridate to provide thetitle compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.84 (d, J=1.8 Hz, 1H),7.68 (s, 1H), 7.46-7.56 (m, 1H), 7.39-7.44 (m, 1H), 7.25-7.32 (m, 1H),6.82 (s, 4H), 5.30-5.39 (m, 1H), 4.45-4.56 (m, 2H), 4.21-4.34 (m, 1H),3.70 (s, 3H), 3.66 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 494.0 (M+H)⁺.

Example 98 but-2-yn-1-yl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

Example 98 was prepared according to the procedure used for thepreparation of Example 53, substituting but-2-yn-1-yl carbonochloridatefor 2-ethylhexyl carbonochloridate to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.80 (d, J=1.9 Hz, 1H), 7.62 (s, 1H), 7.39 (dd,J=8.3, 1.9 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.25 (s, 1H), 5.21-5.27 (m,1H), 4.44-4.55 (m, 4H), 4.13-4.19 (m, 1H), 3.63 (s, 3H), 2.95 (s, 3H),1.72 (t, J=2.3 Hz, 3H). MS (ESI+) m/z 440.1 (M+H)⁺.

Example 993-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamideExample 99a3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoicacid

Example 82 (375 mg, 0.692 mmol) and lithium hydroxide (83 mg, 3.5 mmol)were combined in the mixture of dioxane (6 mL) and water (2 mL). Thereaction mixture was stirred at ambient temperature for 5 hours. Thereaction mixture was diluted with water, the pH adjusted to 4 byaddition of 1M HCl, and extracted by ethyl acetate. The organic layerwas washed with saturated aqueous sodium chloride, dried with anhydroussodium sulfate, filtered and concentrated to afford the title compound(365 mg, 100%).

Example 99b3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide

Example 99a (31.7 mg, 0.060 mmol),2-(6-chloro-1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (49.6 mg, 0.120 mmol) and diisopropylethylamine(0.042 mL, 0.240 mmol) were combined in dimethylformamide (1 mL). Tothis solution was added 0.5M ammonia in dioxane (0.240 mL, 0.120 mmol).The reaction mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was partitioned with ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride twice,dried with anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by reverse phase HPLC (C18, CH₃CN/water (10 mMammonium acetate), 10-100%) to afford the title compound (18 mg, 57%).¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (s, 1H) 7.82 (d, J=1.83 Hz, 1H) 7.68(s, 1H) 7.34 (s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H) 7.01-7.17 (m, 3H)6.86-6.99 (m, 2H) 6.77 (s, 1H) 5.01 (dd, J=9.00, 5.95 Hz, 1H) 4.38-4.55(m, 2H) 3.64 (s, 3H) 2.93 (s, 3H) 2.10-2.20 (m, 2H) 1.87-1.98 (m, 1H)1.31-1.45 (m, 1H). MS (ESI+) m/z 549 (M+Na)⁺.

Example 1004-(4-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 100 was prepared according to the procedure used for thepreparation of Example 54, substituting 4-fluorobenzoyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.83 (d, J=1.9 Hz, 1H), 7.75 (s, 1H), 7.25-7.33 (m, 1H),7.10 (ddd, J=13.0, 8.5, 5.9 Hz, 3H), 6.90-7.03 (m, 3H), 5.66-5.88 (m,1H), 4.33-4.50 (m, 2H), 4.16 (d, J=16.2 Hz, 1H), 3.69 (s, 3H), 2.84 (s,3H). MS (ESI+) m/z 466.1 (M+H)⁺.

Example 1014-(3-methoxypropanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 101 was prepared according to the procedure used for thepreparation of Example 54, substituting 3-methoxypropanoyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.86 (s, 1H), 7.67 (s, 1H), 7.38-7.46 (m, 2H), 7.22-7.25(m, 1H), 5.48-5.61 (m, 1H), 4.52 (q, J=14.0 Hz, 2H), 3.93-4.01 (m, 1H),3.64 (s, 3H), 3.29-3.43 (m, 3H), 3.00 (s, 2H), 2.95 (s, 3H), 2.33-2.43(m, 1H), 1.93-2.02 (m, 1H). MS (ESI+) m/z 430.2 (M+H)⁺.

Example 1024-([1,1′-biphenyl]-4-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 102 was prepared according to the procedure used for thepreparation of Example 54, substituting [1,1′-biphenyl]-4-carbonylchloride for isobutyryl chloride to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.85 (d, J=1.8 Hz, 1H), 7.78 (s, 1H), 7.54 (d,J=7.6 Hz, 2H), 7.39-7.46 (m, 4H), 7.29-7.37 (m, 2H), 7.14 (d, J=8.4 Hz,3H), 6.99-7.06 (m, 1H), 5.70-5.94 (m, 1H), 4.42 (d, J=5.2 Hz, 2H),4.14-4.22 (m, 1H), 3.70 (s, 3H), 2.81 (s, 3H). MS (ESI+) m/z 424.0(M+H)⁺.

Example 1034-(3-cyclopentylpropanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 103 was prepared according to the procedure used for thepreparation of Example 54, substituting 3-cyclopentylpropanoyl chloridefor isobutyryl chloride, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.86 (s, 1H), 7.65 (s, 1H), 7.41 (dd, J=22.9, 9.0 Hz,2H), 7.23 (s, 1H), 5.51-5.59 (m, 1H), 4.52 (q, J=13.6 Hz, 2H), 3.89-3.99(m, 1H), 3.63 (s, 3H), 2.94 (s, 3H), 1.83-2.10 (m, 2H), 1.19-1.40 (m,9H), 0.66-0.80 (m, 2H). MS (ESI+) m/z 468.2 (M+H)⁺.

Example 1044-(2-(3-methoxyphenyl)acetyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 104 was prepared according to the procedure used for thepreparation of Example 54, substituting 2-(3-methoxyphenyl)acetylchloride for isobutyryl chloride to provide the title compound. ¹H NMR(400 MHz, DMSO-d₆/D₂O) δ 7.65-7.74 (m, 1H), 7.39-7.49 (m, 2H), 7.16-7.30(m, 2H), 6.52-6.94 (m, 2H), 6.04-6.18 (m, 1H), 5.49-5.61 (m, 1H),4.45-4.56 (m, 2H), 3.58 (s, 3H), 3.47 (s, 2H), 2.95 (s, 4H). MS (ESI+)m/z 492.1 (M+H)⁺.

Example 10510-methyl-7-((methylsulfonyl)methyl)-4-propionyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 105 was prepared according to the procedure used for thepreparation of Example 54, substituting propionyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.81-7.88 (m, 1H), 7.63-7.69 (m, 1H), 7.37-7.45 (m, 2H),7.22-7.26 (m, 1H), 5.51-5.61 (m, 1H), 4.52 (q, J=13.8 Hz, 2H), 3.91-3.99(m, 1H), 3.63 (s, 3H), 2.95 (s, 3H), 2.13 (dq, J=14.8, 7.3 Hz, 1H),1.64-1.81 (m, 1H), 0.72-0.87 (m, 3H). MS (ESI+) m/z 400.1 (M+H)⁺.

Example 10610-methyl-4-(3-methylbutanoyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 106 was prepared according to the procedure used for thepreparation of Example 54, substituting 3-methylbutanoyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.81-7.88 (m, 1H), 7.63-7.69 (m, 1H), 7.32-7.47 (m, 2H),7.22-7.25 (m, 1H), 5.49-5.62 (m, 1H), 4.47-4.59 (m, 2H), 3.91-3.99 (m,1H), 3.63 (s, 3H), 2.95 (s, 3H), 1.90-2.01 (m, 1H), 1.66-1.81 (m, 1H),0.63-0.69 (m, 3H), 0.43-0.51 (m, 4H). MS (ESI+) m/z 428.1 (M+H)⁺.

Example 1074-(3,3-dimethylbutanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 107 was prepared according to the procedure used for thepreparation of Example 54, substituting 3,3-dimethylbutanoyl chloridefor isobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.85 (s, 1H), 7.65 (s, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.32(d, J=8.4 Hz, 1H), 7.23 (s, 1H), 5.57-5.64 (m, 1H), 3.87-3.97 (m, 1H),4.52 (q, J=13.7 Hz, 2H), 3.63 (s, 3H), 2.94 (s, 3H), 1.84-2.01 (m, 2H),0.69 (s, 9H). MS (ESI+) m/z 442.2 (M+H)⁺.

Example 10810-methyl-7-((methylsulfonyl)methyl)-4-(2-phenylacetyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 108 was prepared according to the procedure used for thepreparation of Example 54, substituting 2-phenylacetyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.69-7.74 (m, 1H), 7.44 (s, 2H), 7.24-7.28 (m, 2H),7.19-7.23 (m, 2H), 6.93-7.01 (m, 2H), 6.54-6.62 (m, 1H), 5.49-5.57 (m,1H), 4.46-4.57 (m, 2H), 3.95-4.01 (m, 1H), 3.58 (s, 3H), 2.96 (s, 5H).MS (ESI+) m/z 462.1 (M+H)⁺.

Example 1094-benzoyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 109 was prepared according to the procedure used for thepreparation of Example 54, substituting benzoyl chloride for isobutyrylchloride to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆/D₂O) δ7.90-7.96 (m, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.75 (s, 1H), 7.20-7.34 (m,2H), 7.09-7.18 (m, 2H), 7.04 (d, J=7.4 Hz, 2H), 6.92-7.01 (m, 1H),5.65-5.87 (m, 1H), 4.41 (d, J=5.0 Hz, 2H), 4.11-4.21 (m, 1H), 3.69 (s,3H), 2.82 (s, 3H). MS (ESI+) m/z 448.0 (M+H)⁺.

Example 1104-(4-methoxybenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 110 was prepared according to the procedure used for thepreparation of Example 54, substituting 4-methoxybenzoyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.83 (d, J=1.8 Hz, 1H), 7.75 (s, 1H), 7.27 (s, 1H), 7.14(dd, J=8.0, 2.1 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.1 Hz, 1H),6.68 (d, J=8.8 Hz, 2H), 5.72-5.92 (m, 1H), 4.36-4.49 (m, 2H), 4.12 (d,J=14.4 Hz, 1H), 3.68 (d, J=5.3 Hz, 6H), 2.85 (s, 3H). MS (ESI+) m/z478.1 (M+H)⁺.

Example 111 methyl4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)-4-oxobutanoate

Example 111 was prepared according to the procedure used for thepreparation of Example 54, substituting methyl 4-chloro-4-oxobutanoatefor isobutyryl chloride, to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.85-7.89 (m, 1H), 7.66-7.71 (m, 1H), 7.42-7.47 (m, 2H),7.21-7.25 (m, 1H), 5.49-5.58 (m, 1H), 4.47-4.58 (m, 2H), 3.93-4.01 (m,1H), 3.64 (s, 3H), 3.40-3.44 (m, 2H), 2.95 (s, 3H), 2.28-2.49 (m, 2H),1.84-2.00 (m, 1H). MS (ESI+) m/z 458.1 (M+H)⁺.

Example 1124-(2,4-difluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 112 was prepared according to the procedure used for thepreparation of Example 54, substituting 2,4-difluorobenzoyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.79 (s, 1H), 7.70 (s, 1H), 7.29-7.38 (m, 1H), 7.00-7.17(m, 3H), 6.78-6.95 (m, 2H), 5.74-5.85 (m, 1H), 4.33-4.47 (m, 2H),4.14-4.24 (m, 1H), 3.67 (s, 3H), 2.81 (s, 3H). MS (ESI+) m/z 484.1(M+H)⁺.

Example 1134-(2-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 113 was prepared according to the procedure used for thepreparation of Example 54, substituting 2-fluorobenzoyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.80-7.86 (m, 1H), 7.70 (s, 1H), 7.58-7.64 (m, 1H),7.30-7.40 (m, 1H), 7.17-7.28 (m, 1H), 6.99-7.14 (m, 2H), 6.83-6.99 (m,2H), 5.72-5.88 (m, 1H), 4.26-4.49 (m, 2H), 4.12-4.25 (m, 1H), 3.68 (s,3H), 2.77 (s, 3H). MS (ESI+) m/z 466.0 (M+H)⁺.

Example 1144-(1-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 114 was prepared according to the procedure used for thepreparation of Example 54, substituting 1-naphthoyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.74-7.81 (m, 1H), 7.66-7.73 (m, 1H), 7.60-7.67 (m, 1H),7.52-7.60 (m, 2H), 7.38-7.49 (m, 2H), 7.16-7.32 (m, 2H), 6.94-7.07 (m,2H), 6.84-6.92 (m, 1H), 5.89-6.00 (m, 1H), 4.33-4.61 (m, 1H), 4.20-4.30(m, 2H), 3.69 (s, 3H), 2.59-2.76 (m, 3H). MS (ESI+) m/z 498.1 (M+H)⁺.

Example 1154-(cyclopropanecarbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 115 was prepared according to the procedure used for thepreparation of Example 54, substituting cyclopropanecarbonyl chloridefor isobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.83-7.91 (m, 1H), 7.63-7.71 (m, 1H), 7.39-7.47 (m, 2H),7.18-7.27 (m, 1H), 5.53-5.66 (m, 1H), 4.44-4.61 (m, 2H), 3.89-4.05 (m,1H), 3.64 (s, 3H), 2.96 (s, 3H), 1.91-1.98 (m, 1H), 1.18-1.32 (m, 1H),1.04-1.15 (m, 2H), 0.55-0.66 (m, 1H). MS (ESI+) m/z 412.1 (M+H)⁺.

Example 11610-methyl-7-((methylsulfonyl)methyl)-4-(3-phenylpropanoyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 116 was prepared according to the procedure used for thepreparation of Example 54, substituting 3-phenylpropanoyl chloride forisobutyryl chloride to provide the title compound. ¹H NMR (400 MHz,DMSO-d₆/D₂O) δ 7.83 (d, J=0.6 Hz, 1H), 7.59 (s, 1H), 7.40 (d, J=9.5 Hz,1H), 7.31 (d, J=8.3 Hz, 1H), 7.23 (s, 1H), 6.97-7.06 (m, 3H), 6.76-6.84(m, 2H), 5.51-5.63 (m, 1H), 4.51 (q, J=13.9 Hz, 2H), 3.89-4.01 (m, 1H),3.63 (s, 3H), 2.93 (s, 3H), 2.61 (t, J=7.8 Hz, 2H), 2.33-2.43 (m, 1H),2.02-2.14 (m, 1H). MS (ESI+) m/z 476.2 (M+H)⁺.

Example 1172-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione

Example 12d (0.4 g, 0.902 mmol) and2-(1,3-dioxoisoindolin-2-yl)acetaldehyde (0.683 g, 3.61 mmol) werecombined in tetrahydrofuran (9.02 mL) under nitrogen, cooled to 0° C.and treated drop-wise with 1M titanium(IV) chloride in dichloromethane(3.61 mL, 3.61 mmol) to give an opaque red solution. The solution wasstirred for 72 hours at ambient temperature and partitioned betweenethyl acetate and water. The organic layer was washed with saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, filteredand concentrated. Purification by chromatography (silica gel, 0.5-5%methanol in dichloromethane) afforded the title compound as a yellowpowder (0.45 g, 81%). ¹H NMR (500 MHz, DMSO-d₆) δ 11.78 (d, J=1.83 Hz,1H), 7.93 (d, J=1.53 Hz, 1H), 7.81-7.86 (m, 4H), 7.76 (s, 1H), 7.24-7.30(m, 1H), 7.21 (dd, J=8.24, 1.83 Hz, 1H), 7.09-7.15 (m, 1H) 6.99-7.05 (m,1H), 6.96 (d, J=2.44 Hz, 1H), 6.92 (d, J=8.24 Hz, 1H), 5.44 (dd, J=9.92,5.34 Hz, 1H), 4.51-4.56 (m, 1H), 4.44-4.48 (m, 1H), 3.87 (dd, J=13.28,5.34 Hz, 1H), 3.66 (s, 3H), 3.52 (dd, J=13.28, 10.22 Hz, 1H), 2.98 (s,3H). MS (ESI+) m/z 615 (M+H)⁺.

Example 1183-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-methylpropanamide

Example 118 was prepared according to the procedure used for thepreparation of Example 99b, substituting methanamine for ammonia.Purification by reverse phase HPLC (C18, CH₃CN/water (10 mM ammoniumacetate), 20-100%) afforded the title compound (22 mg, 68%). ¹H NMR (400MHz, DMSO-d₆) δ 11.90 (d, J=1.22 Hz, 1H) 7.82 (d, J=1.83 Hz, 1H) 7.77(q, J=4.48 Hz, 1H) 7.68 (s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H) 7.02-7.12(m, 3H) 6.87-7.00 (m, 2H) 5.00 (dd, J=9.00, 5.95 Hz, 1H) 4.33-4.58 (m,2H) 3.64 (s, 3H) 2.93 (s, 3H) 2.55 (d, J=4.58 Hz, 3H) 2.07-2.22 (m, 2H)1.83-2.00 (m, 1H) 1.31-1.48 (m, 1H). MS (ESI+) m/z 563 (M+Na)⁺.

Example 1193-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N,N-dimethylpropanamide

Example 119 was prepared according to the procedure used for thepreparation of Example 99b, substituting dimethylamine for ammonia.Purification by reverse phase HPLC (C18, CH₃CN/water (10 mM ammoniumacetate), 20-100%) afforded the title compound (24 mg, 72%). ¹H NMR (400MHz, DMSO-d₆) δ 11.89 (s, 1H) 7.83 (d, J=1.83 Hz, 1H) 7.68 (s, 1H) 7.22(dd, J=8.24, 2.14 Hz, 1H) 7.13-7.20 (m, 1H) 7.11 (s, 1H) 7.02-7.10 (m,1H) 6.97 (d, J=8.24 Hz, 1H) 6.88-6.96 (m, 1H) 5.03-5.12 (m, 1H)4.37-4.57 (m, 2H) 3.64 (s, 3H) 2.94 (s, 3H) 2.87 (s, 3H) 2.80 (s, 3H)2.28-2.46 (m, 2H) 1.85-1.95 (m, 1H) 1.37-1.52 (m, 1H). MS (ESI+) m/z 577(M+Na)⁺.

Example 1204-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-morpholino-3-oxopropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 120 was prepared according to the procedure used for thepreparation of Example 99b, substituting morpholine for ammonia.Purification by reverse phase HPLC (C18, CH₃CN/water (10 mM ammoniumacetate), 20-100%) afforded the title compound (28 mg, 78%). ¹H NMR (500MHz, DMSO-d₆) δ 11.89 (s, 1H) 7.83 (d, J=1.83 Hz, 1H) 7.68 (s, 1H) 7.22(dd, J=8.24, 1.83 Hz, 1H) 7.03-7.16 (m, 3H) 6.99 (d, J=8.24 Hz, 1H)6.88-6.94 (m, 1H) 5.08 (t, J=7.63 Hz, 1H) 4.39-4.57 (m, 2H) 3.64 (s, 3H)3.37-3.55 (m, 8H) 2.94 (s, 3H) 2.40-2.48 (m, 1H) 2.29-2.39 (m, 1H)1.84-1.94 (m, 1H) 1.38-1.55 (m, 1H). MS (ESI+) m/z 619 (M+Na)⁺.

Example 1213-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(tetrahydro-2H-pyran-4-yl)propanamide

Example 121 was prepared according to the procedure used for thepreparation of Example 99b, substituting tetrahydro-2H-pyran-4-amine forammonia. Purification by reverse phase HPLC (C18, CH₃CN/water (10 mMammonium acetate), 20-100%) afforded the title compound (28 mg, 76%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.90 (s, 1H) 7.86 (d, J=7.63 Hz, 1H) 7.82 (d,J=1.83 Hz, 1H) 7.68 (s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H) 7.02-7.13 (m,3H) 6.87-6.98 (m, 2H) 5.00 (dd, J=9.16, 5.80 Hz, 1H) 4.36-4.57 (m, 2H)3.70-3.85 (m, 3H) 3.64 (s, 3H) 2.93 (s, 3H) 2.16 (t, J=7.17 Hz, 2H)1.89-2.00 (m, 1H) 1.58-1.73 (m, 2H) 1.27-1.45 (m, 3H). MS (ESI+) m/z 633(M+Na)⁺.

Example 1223-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N′-methyl-N′-phenylpropanehydrazide

Example 122 was prepared according to the procedure used for thepreparation of Example 99b, substituting 1-methyl-1-phenylhydrazine forammonia. Purification by reverse phase HPLC (C18, CH₃CN/water (10 mMammonium acetate), 30-100%) afforded the title compound (20 mg, 53%). ¹HNMR (500 MHz, DMSO-d₆) δ 11.95 (d, J=1.83 Hz, 1H) 9.95 (s, 1H) 7.85 (d,J=1.83 Hz, 1H) 7.70 (s, 1H) 7.25 (dd, J=8.24, 1.83 Hz, 1H) 7.13-7.19 (m,3H) 6.97-7.12 (m, 3H) 6.83-6.92 (m, 1H) 6.64-6.75 (m, 3H) 5.05 (dd,J=8.85, 6.10 Hz, 1H) 4.39-4.56 (m, 2H) 3.65 (s, 3H) 3.05 (s, 3H) 2.93(s, 3H) 2.22-2.32 (m, 2H) 1.92-2.01 (m, 1H) 1.43-1.54 (m, 1H). MS (ESI+)m/z 654 (M+Na)⁺.

Example 123N-benzyl-3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide

Example 123 was prepared according to the procedure used for thepreparation of Example 99b, substituting phenylmethanamine for ammonia.Purification by reverse phase HPLC (C18, CH₃CN/water (10 mM ammoniumacetate), 30-100%) afforded the title compound (26 mg, 70%). ¹H NMR (400MHz, DMSO-d₆) δ 11.91 (d, J=2.14 Hz, 1H) 8.39 (t, J=5.95 Hz, 1H) 7.83(d, J=1.83 Hz, 1H) 7.68 (s, 1H) 7.27-7.33 (m, 2H) 7.19-7.25 (m, 4H)7.02-7.11 (m, 3H) 6.97 (d, J=7.93 Hz, 1H) 6.81-6.92 (m, 1H) 5.02 (dd,J=9.00, 5.95 Hz, 1H) 4.38-4.57 (m, 2H) 4.25 (d, J=5.80 Hz, 2H) 3.64 (s,3H) 2.93 (s, 3H) 2.25 (t, J=7.48 Hz, 2H) 1.91-2.02 (m, 1H) 1.35-1.56 (m,1H). MS (ESI+) m/z 639 (M+Na)⁺.

Example 1243-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)propanamide

Example 124 was prepared according to the procedure used for thepreparation of Example 99b, substituting 3-aminotetrahydrothiophene1,1-dioxide for ammonia. Purification by reverse phase HPLC (C18,CH₃CN/water (10 mM ammonium acetate), 20-100%) afforded the titlecompound (27 mg, 70%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H) 8.31(dd, J=6.71, 3.66 Hz, 1H) 7.83 (s, 1H) 7.68 (s, 1H) 7.22 (dd, J=8.24,1.83 Hz, 1H) 7.01-7.13 (m, 3H) 6.88-6.98 (m, 2H) 4.95-5.05 (m, 1H)4.38-4.55 (m, 3H) 3.64 (s, 3H) 3.36-3.44 (m, 1H) 3.23-3.29 (m, 1H)3.06-3.18 (m, 1H) 2.93 (s, 3H) 2.78-2.92 (m, 1H) 2.27-2.40 (m, 1H)2.14-2.24 (m, 2H) 1.87-2.05 (m, 2H) 1.37-1.51 (m, 1H). MS (ESI+) m/z 667(M+Na)⁺.

Example 125 tert-butyl4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoyl)piperazine-1-carboxylate

Example 125 was prepared according to the procedure used for thepreparation of Example 99b, substituting tert-butylpiperazine-1-carboxylate for ammonia. Purification by reverse phase HPLC(C18, CH₃CN/water (10 mM ammonium acetate), 30-100%) afforded the titlecompound (46 mg, 74%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (d, J=1.53 Hz,1H) 7.83 (d, J=1.83 Hz, 1H) 7.68 (s, 1H) 7.23 (dd, J=8.24, 1.53 Hz, 1H)7.11-7.19 (m, 2H) 7.03-7.11 (m, 1H) 6.98 (d, J=8.24 Hz, 1H) 6.87-6.95(m, 1H) 5.08 (t, J=7.63 Hz, 1H) 4.39-4.56 (m, 2H) 3.64 (s, 3H) 3.38-3.44(m, 2H) 3.24-3.30 (m, 6H) 2.93 (s, 3H) 2.32-2.46 (m, 2H) 1.84-1.98 (m,1H) 1.43-1.52 (m, 1H) 1.40 (s, 9H). MS (ESI+) m/z 696 (M+H)⁺.

Example 126 tert-butyl4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamido)piperidine-1-carboxylate

Example 126 was prepared according to the procedure used for thepreparation of Example 99b, substituting tert-butyl4-aminopiperidine-1-carboxylate for ammonia. Purification by reversephase HPLC (C18, CH₃CN/water (10 mM ammonium acetate), 30-100%) affordedthe title compound (48 mg, 75%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (d,J=2.44 Hz, 1H) 7.80-7.85 (m, 2H) 7.68 (s, 1H) 7.22 (dd, J=8.24, 1.83 Hz,1H) 7.02-7.13 (m, 3H) 6.88-6.98 (m, 2H) 5.00 (dd, J=9.16, 6.10 Hz, 1H)4.34-4.55 (m, 2H) 3.76-3.86 (m, 2H) 3.68-3.75 (m, 1H) 3.64 (s, 3H) 2.93(s, 3H) 2.73-2.88 (m, 2H) 2.15 (t, J=7.02 Hz, 2H) 1.88-1.99 (m, 1H)1.61-1.73 (m, 2H) 1.34-1.48 (m, 10H) 1.11-1.27 (m, 2H). MS (ESI+) m/z732 (M+Na)⁺.

Example 1274-(4-chlorophenyl)-N-ethyl-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamideExample 127a 2-bromo-N-(4-chlorophenyl)aniline

Example 127a was prepared according to the procedure used for thepreparation of Example 58h, substituting 2-bromoaniline for Example 58g,to provide the title compound.

Example 127b ethyl1-benzyl-4-(2-((4-chlorophenyl)amino)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 127b was prepared according to the procedure used for thepreparation of Example 5d, substituting Example 127a for Example 5c, andExample 58f for Example if, respectively, to provide the title compound.

Example 127c ethyl4-(2-((4-chlorophenyl)amino)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 127c was prepared according to the procedure used for thepreparation of Example 58j, substituting Example 127b for Example 58i,to provide the title compound.

Example 127d ethyl4-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate

Example 127d was prepared according to the procedure used for thepreparation of Example 58k, substituting Example 127c for Example 58j,to provide the title compound.

Example 127e4-(4-chlorophenyl)-N-ethyl-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

A mixture of Example 127d (150 mg, 0.346 mmol) and ethanamine (25% inethanol wt/wt) (5 mL, 0.832 mmol) was sealed and heated at 78° C. for 2days. The reaction mixture was cooled to ambient temperature andconcentrated. The residue was purified by reverse phase HPLC (C18,CH₃CN/water (0.1% TFA), 0-100% gradient) to give the title compound (18mg, 0.042 mmol, 12.03% yield) as pale solid. ¹H NMR (400 MHz, CDCl₃): δ12.37 (s, 1H), 8.50 (s, 1H), 7.69 (d, J=4.2 Hz, 1H), 7.43 (m, 3H), 7.27(m, 1H), 6.92 (d, J=8.8 Hz, 2H), 6.46 (d, J=8.3 Hz, 2H), 6.13 (d, J=15.3Hz, 1H), 4.53 (m, 1H), 3.76 (s, 3H), 3.58 (m, 2H), 1.32 (m, 3H). MS(ESI+) m/z 433.0 (M+H)⁺

Example 1286-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)hexylacetate

7-oxoheptyl acetate (0.155 g, 0.902 mmol) and Example 12d (0.1 g, 0.225mmol) were combined in tetrahydrofuran (2.255 mL) under nitrogen at 5°C., and treated drop-wise with 1 M titanium(IV) chloride indichloromethane (0.676 mL, 0.676 mmol) to afford a deep red reactionmixture. The reaction mixture was stirred at ambient temperature for 18hours and partitioned between ethyl acetate and water. The organic layerwas washed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, filtered and concentrated.

Purification by chromatography (silica gel, 0.5-4% methanol indichloromethane) afforded the title compound (0.108 g, 80%). ¹H NMR (500MHz, DMSO-d₆) δ 11.85 (s, 1H), 7.84 (s, 1H), 7.67 (s, 1H), 7.23 (d,J=7.93 Hz, 1H), 7.13 (s, 1H), 7.04-7.10 (m, 1H), 6.98 (d, J=7.93 Hz,1H), 6.84 (d, J=5.49 Hz, 2H), 5.00 (t, J=6.56 Hz, 1H), 4.40-4.56 (m,2H), 3.92 (t, J=6.56 Hz, 2H) 3.64 (s, 3H), 2.92 (s, 3H), 1.96 (s, 3H),1.09-1.67 (m, 10H). MS (ESI+) m/z 598 (M+H)⁺.

Example 1293-(aminomethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 117 (0.45 g, 0.732 mmol) and hydrazine hydrate (0.733 g, 14.64mmol) were combined in ethanol (14.64 mL) and stirred at reflux for 2hours. The solution was allowed to cool to ambient temperature and theresulting white solid was removed by filtration. The filtrate wasconcentrated to a residue. Purification of the residue by reverse phaseHPLC (C18, CH₃CN/10 mM ammonium acetate in water, 10-100% gradient)afforded the title compound (0.280 mg, 80%). ¹H NMR (500 MHz, DMSO-d₆) δ11.84 (s, 1H), 7.82 (d, J=1.83 Hz, 1H), 7.67 (s, 1H), 7.24-7.30 (m, 1H),7.22 (dd, J=8.09, 1.98 Hz, 1H), 7.15 (s, 1H), 7.00-7.06 (m, 2H),6.89-6.95 (m, 1H), 5.02 (dd, J=8.24, 6.41 Hz, 1H), 4.41-4.55 (m, 2H),3.64 (s, 3H), 3.57 (s, 1H), 2.94 (s, 3H), 2.69 (dd, J=12.97, 8.70 Hz,1H), 2.45 (dd, J=12.97, 6.26 Hz, 1H). MS (ESI+) m/z 485 (M+H)⁺.

Example 130N-((((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)(dimethylamino)methylene)-N-methylmethanaminium

Example 129 (0.03 g, 0.062 mmol),N-((((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)(dimethylamino)methylene)-N-methylmethanaminium(HCTU, 0.033 g, 0.080 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.032mL, 0.186 mmol) were combined in DMF (0.619 mL). To the mixture wasadded acetic acid (10.63 μL, 0.186 mmol) and the mixture was stirred for1 hour and partitioned between ethyl acetate and water. The organiclayer was washed with saturated aqueous sodium chloride, dried overanhydrous sodium sulfate, filtered and concentrated. Purification byreverse phase HPLC (C18, CH₃CN/0.1% TFA in water, 10-100% gradient)afforded the title compound as a trifluoroacetate salt (0.03 g, 78%). ¹HNMR (500 MHz, PYRIDINE-d₆) δ 13.11 (s, 1H), 9.84 (s, 1H), 8.08 (d,J=1.47 Hz, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.43-7.49 (m, 2H), 7.20 (d,J=8.07 Hz, 1H), 6.82-6.89 (m, 1H), 6.74-6.79 (m, 1H), 5.95-6.00 (m, 1H),4.65 (s, 2H), 3.73 (dd, J=13.48, 8.71 Hz, 1H), 3.61 (s, 3H), 3.57 (dd,J=13.48, 6.33 Hz, 1H), 3.08 (s, 3H), 2.77 (s, 12H). MS (ESI+) m/z 583(M)⁺.

Example 1314-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-oxo-3-(piperazin-1-yl)propyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To a mixture of Example 125 (40 mg, 0.057 mmol) in dichloromethane (1.5mL) was added trifluoroacetic acid (0.50 mL, 6.5 mmol). The reactionmixture was stirred at ambient temperature for 30 minutes andconcentrated. To the residue was added water, the pH was adjusted to 7by addition of saturated aqueous sodium bicarbonate, and the mixture wassonicated for 5 minutes, filtered, washed with water, and dried toprovide the title compound (18 mg, 53%). ¹H NMR (500 MHz, DMSO-d₆) δ11.89 (s, 1H) 7.83 (d, J=1.83 Hz, 1H) 7.68 (s, 1H) 7.22 (dd, J=8.24,1.83 Hz, 1H) 7.03-7.18 (m, 3H) 6.97 (d, J=7.93 Hz, 1H) 6.87-6.94 (m, 1H)5.08 (t, J=7.63 Hz, 1H) 4.39-4.60 (m, 2H) 3.64 (s, 3H) 3.18-3.25 (m, 2H)2.94 (s, 3H) 2.55-2.61 (m, 4H) 2.27-2.46 (m, 3H) 1.83-1.94 (m, 1H)1.38-1.57 (m, 1H). MS (ESI+) m/z 596 (M+H)⁺.

Example 1323-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(piperidin-4-yl)propanamide

To a mixture of Example 126 (42 mg, 0.059 mmol) in dichloromethane (1.5mL) was added trifluoroacetic acid (0.50 mL, 6.5 mmol). The reactionmixture was stirred at ambient temperature for 30 minutes andconcentrated. The residue was purified by reverse phase HPLC (C18,CH₃CN/water (10 mM ammonium acetate), 20-100% gradient) to provide thetitle compound (15 mg, 42%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.77-7.86 (m,2H) 7.68 (s, 1H) 7.22 (dd, J=8.24, 1.83 Hz, 1H) 7.01-7.13 (m, 3H)6.85-6.99 (m, 2H) 5.00 (dd, J=9.16, 6.10 Hz, 1H) 4.38-4.56 (m, 2H)3.57-3.67 (m, 4H) 3.39-3.52 (m, 1H) 2.90-2.99 (m, 5H) 2.51-2.58 (m, 2H)2.15 (t, J=7.17 Hz, 2H) 1.89-1.97 (m, 1H) 1.62-1.72 (m, 2H) 1.36-1.46(m, 1H) 1.20-1.35 (m, 2H). MS (ESI+) m/z 610 (M+H)⁺.

Example 1334-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)butane-1,2-diyldiacetate

5-Oxopentane-1,2-diyl diacetate (0.182 g, 0.902 mmol) and Example 12d(0.1 g, 0.225 mmol) were combined in tetrahydrofuran (2.2 mL) undernitrogen at 5° C., and treated dropwise with 1 M titanium(IV) chloridein toluene (0.676 mL, 0.676 mmol). The reaction mixture was stirred atambient temperature for 18 hours and partitioned between ethyl acetateand water. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered andconcentrated. Purification by reverse phase HPLC (C18, CH₃CN/0.1% TFA inwater, 10-100% gradient) afforded the title compound (0.038 g, 26%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.87 (s, 1H), 7.83-7.87 (m, 1H), 7.69 (s, 1H),7.22-7.28 (m, 1H), 6.96-7.18 (m, 3H), 6.69-6.87 (m, 2H), 5.01 (t, J=6.71Hz, 1H), 4.78-4.92 (m, 1H), 4.40-4.56 (m, 2H), 3.85-4.08 (m, 2H), 3.64(s, 3H), 2.92 (s, 3H), 1.95 (s, 3H), 1.88 (s, 3H), 1.30-1.79 (m, 4H). MS(ESI⁺) m/z 628 (M+H)⁺.

Example 134 methyl5-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)pentanoate

Methyl 6-oxohexanoate (0.130 g, 0.902 mmol) and Example 12d (0.1 g,0.225 mmol) were combined in tetrahydrofuran (2.3 mL) under nitrogen at5° C., and treated dropwise with 1 M titanium(IV) chloride (0.676 mL,0.676 mmol) in dichloromethane. The reaction mixture was stirred atambient temperature for 18 hours and partitioned between ethyl acetateand water. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered andconcentrated. Purification by reverse phase HPLC (C18, CH₃CN/0.1% TFA inwater, 10-100% gradient) afforded the title compound (0.069 g, 54%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.84 (d, J=1.83 Hz, 1H), 7.85 (d, J=1.53 Hz,1H), 7.68 (s, 1H), 7.24 (dd, J=8.24, 1.83 Hz, 1H), 7.13 (d, J=2.44 Hz,1H), 7.03-7.11 (m, 1H), 6.98 (d, J=8.24 Hz, 1H), 6.76-6.88 (m, 2H), 4.99(t, J=7.32 Hz, 1H), 4.42-4.55 (m, 2H), 3.64 (s, 3H), 3.54 (s, 3H), 2.92(s, 3H), 2.19 (t, J=6.71 Hz, 2H), 1.21-1.66 (m, 6H). MS (ESI⁺) m/z 570(M+H)⁺.

Example 135 tert-butyl(2-(((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)-2-oxoethyl)carbamate

2-((Tert-butoxycarbonyl)amino)acetic acid (0.022 g, 0.124 mmol),N-ethyl-N-isopropylpropan-2-amine (0.032 mL, 0.186 mmol) and2-(6-chloro-1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (HCTU, 0.028 g, 0.068 mmol) were combined inN,N-dimethylformamide (0.619 mL) and stirred at ambient temperature for15 minutes. To this solution was added dropwise a solution of Example129 (0.03 g, 0.062 mmol) dissolved in N,N-dimethylformamide (0.619 mL).The reaction mixture was stirred for 2 hours at ambient temperature andpartitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, filtered and concentrated. Purification by reverse phaseHPLC (C18, CH₃CN/10 mM ammonium acetate in water, 10-100% gradient)afforded the title compound (0.02 g, 50%). ¹H NMR (400 MHz, DMSO-d₆) δ11.93 (s, 1H), 7.82 (m, 1H), 7.81 (d, J=1.83 Hz, 1H), 7.69 (s, 1H),7.33-7.46 (m, 1H), 7.20 (dd, J=8.24, 1.83 Hz, 1H), 7.12 (s, 1H),6.93-7.09 (m, 4H), 5.20 (dd, J=8.39, 6.26 Hz, 1H), 4.39-4.53 (m, 2H),3.65 (s, 3H), 3.53 (d, J=6.10 Hz, 2H), 2.92 (s, 3H), 2.82-2.91 (m, 2H),2.48-2.51 (m, 9H). MS (ESI⁺) m/z 640 (M+H)⁺.

Example 1364-(2,4-difluorophenyl)-3-(6-hydroxyhexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

The product from Example 128 (0.08 g, 0.134 mmol) and lithium hydroxidemonohydrate (0.056 g, 1.339 mmol) were combined in tetrahydrofuran(1.785 mL)/water (0.892 mL) and the reaction mixture was stirred for 2hours at 50° C. The reaction mixture was cooled to ambient temperatureand partitioned between ethyl acetate and water and the pH was adjustedto 7 by careful addition of aqueous 1 M HCl. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, filtered and concentrated. Purification by reverse phaseHPLC (C18, CH₃CN/0.1% TFA in water, 10-100% gradient) afforded the titlecompound (0.05 g, 67%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 7.84(d, J=1.83 Hz, 1H), 7.67 (s, 1H), 7.23 (dd, J=8.09, 1.98 Hz, 1H), 7.12(d, J=2.44 Hz, 1H), 7.03-7.10 (m, 1H), 6.98 (d, J=8.24 Hz, 1H),6.78-6.89 (m, 2H), 5.00 (t, J=7.17 Hz, 1H), 4.41-4.54 (m, 2H), 4.32 (t,J=6.56 Hz, 1H), 3.64 (s, 3H), 3.31 (t, J=6.56 Hz, 2H), 2.92 (s, 3H),1.20-1.67 (m, 10H). MS (ESI+) m/z 556 (M+H)⁺.

Example 137N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)benzamide

The product from Example 129 (0.03 g, 0.062 mmol),N-ethyl-N-isopropylpropan-2-amine (0.216 mL, 1.238 mmol) and benzoylchloride (0.036 mL, 0.310 mmol) were combined in N,N-dimethylformamide(1.238 mL) and heated at 50° C. for 2 hours. The reaction mixture wascooled to ambient temperature and partitioned between ethyl acetate andwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered andconcentrated. Purification by reverse phase HPLC (C18, CH₃CN/0.1% TFA inwater, 10-100% gradient) afforded the title compound (0.023 g, 63%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.86 (d, J=2.44 Hz, 1H), 8.55 (t, J=5.49 Hz,1H), 7.84 (d, J=1.83 Hz, 1H), 7.81 (s, 1H), 7.79 (d, J=1.53 Hz, 1H),7.72 (s, 1H), 7.44-7.56 (m, 4H), 7.21 (dd, J=8.24, 1.83 Hz, 1H),7.02-7.12 (m, 2H), 6.99 (d, J=2.75 Hz, 1H), 6.94 (d, J=8.24 Hz, 1H),5.42 (dd, J=9.61, 5.34 Hz, 1H), 4.40-4.55 (m, 2H), 3.66 (s, 3H),2.96-3.06 (m, 2H), 2.94 (s, 3H). MS (ESI+) m/z 589 (M+H)⁺.

Example 1381-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)-3-phenylurea

The product from Example 129 (0.03 g, 0.062 mmol),N-ethyl-N-isopropylpropan-2-amine (0.054 mL, 0.310 mmol) and phenylisocyanate (6.77 μL, 0.062 mmol) were combined in tetrahydrofuran (1.238mL) and stirred for 30 minutes at ambient temperature. The reactionmixture was concentrated and the residue was purified by reverse phaseHPLC (C18, CH₃CN/0.1% TFA in water, 10-100% gradient) to afford thetitle compound (0.021 g, 56%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.96 (d,J=2.44 Hz, 1H), 8.71 (s, 1H), 7.85 (d, J=1.83 Hz, 1H), 7.72 (s, 1H),7.41 (d, J=7.63 Hz, 2H), 7.17-7.28 (m, 4H), 7.15 (d, J=2.75 Hz, 1H),7.03-7.11 (m, 2H), 6.88-6.98 (m, 2H), 6.12 (t, J=5.65 Hz, 1H), 5.25 (t,J=7.48 Hz, 1H), 4.42-4.56 (m, 2H), 3.65 (s, 3H), 3.22-3.31 (m, 1H),3.00-3.08 (m, 1H), 2.94 (s, 3H). MS (ESI+) m/z 602 (M+H)⁺.

Example 1392-amino-N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)acetamide

The product from Example 135 (0.01 g, 0.016 mmol) in a mixture ofdichloromethane (2 mL)/TFA (1.0 mL) was stirred at ambient temperaturefor 1 hour, concentrated and azeotroped three times with toluene toafford the title compound as the TFA salt (0.01 g, 98%). ¹H NMR (400MHz, DMSO-d₆) δ 12.03 (d, J=2.44 Hz, 1H), 8.45 (t, J=5.80 Hz, 1H), 8.00(s, 2H), 8.00 (s, 1H), 7.83 (d, J=1.83 Hz, 1H), 7.72 (s, 1H), 6.92-7.40(m, 5H) 5.18 (dd, J=9.16, 5.49 Hz, 1H), 4.40-4.55 (m, 2H), 3.65 (s, 3H),3.43-3.67 (m, 4H), 2.94 (s, 3H). MS (ESI+) m/z 542 (M+H)⁺.

Example 1404-(2,4-difluorophenyl)-3-(3,4-dihydroxybutyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

The product from Example 133 (0.038 g, 0.061 mmol) and lithium hydroxide(0.029 g, 1.211 mmol) were combined in tetrahydrofuran (1.614 mL)/water(0.807 mL) and stirred for 2 hours at 50° C. The reaction mixture wascooled to ambient temperature and partitioned between ethyl acetate andwater and the pH was adjusted to 7 by careful addition of aqueous 1 MHCl. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered and concentratedto afford the title compound (0.028 g, 85%). ¹H NMR (500 MHz, DMSO-d₆) δ11.85 (s, 1H), 7.83 (d, J=1.83 Hz, 1H), 7.67 (s, 1H), 7.19-7.25 (m, 1H),7.11 (dd, J=5.04, 2.59 Hz, 1H), 7.03-7.09 (m, 1H), 6.84-6.99 (m, 3H),4.97-5.04 (m, 1H), 4.43-4.53 (m, 2H), 4.34-4.41 (m, J=13.28, 1.98 Hz,2H), 3.64 (s, 3H), 3.10-3.30 (m, 3H), 2.92 (s, 3H), 1.19-1.86 (m, 4H).MS (ESI+) m/z 544 (M+H)⁺.

Example 1414-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamideExample 141a

ethyl4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate

Example 141a was prepared according to the procedure used for thepreparation of Example 82, substituting ethyl glyoxylate for methyl4-oxobutanoate, to provide the title compound as a white solid.

Example 141b4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylicacid

A 250 mL round-bottomed flask was charged with Example 141a (0.6446 g,1.222 mmol), dioxane (9.16 mL) and water (3.05 mL) to give a yellowsolution. Lithium hydroxide hydrate (0.256 g, 6.11 mmol) was added. Thereaction mixture was stirred at ambient temperature for 72 hours. Thereaction mixture was quenched with 1N HCl. The resulting suspension wasstirred for 15 minutes, and filtered. The solid was rinsed with water,dried overnight at ambient temperature, and then dried in a 60° C.vacuum oven for 72 hours to provide the title compounds as a yellowsolid (0.5521 g, 90% yield).

Example 141c4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

A 250 mL round-bottomed flask was charged with Example 141b (0.0473 g,0.095 mmol) and dichloromethane (1.894 mL) to give a tan solution.Oxalyl dichloride (0.021 mL, 0.237 mmol) and N,N-dimethylformamide(0.733 μL, 9.47 μmol) were added. The reaction mixture was stirred atambient temperature for 2 hours and then cooled to 0° C. Ammoniumhydroxide (0.186 mL, 4.73 mmol) was added. The reaction mixture wasstirred at 0° C. for 15 minutes, and stirred at ambient temperatureovernight. The reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The reaction mixture was purified by HPLC (Phenomenex LunaC8(2) 5 μm 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile(A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rateof 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min linear gradient 10-95% A,7.0-10.0 min 95% A, 10.0-12.0 min linear gradient 95-10% A). Sampleswere injected in 1.5 mL DMSO:methanol (1:1))) to provide the titlecompound as a white solid (7.0 mg, 15% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 11.96-12.01 (m, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.66 (s, 1H), 7.49-7.59(m, 1H), 7.30 (d, J=2.7 Hz, 1H), 7.10-7.16 (m, 2H), 6.93-7.11 (m, 3H),6.89 (d, J=8.2 Hz, 1H), 6.68 (bs, 1H), 5.75 (s, 1H), 4.36-4.50 (m, 2H),2.91 (s, 3H). MS (ESI+) m/z 499.1 (M+H)⁺.

Example 1424-(2,4-difluorophenyl)-3-(3-hydroxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To a solution of Example 82 (542 mg, 1.00 mmol) in tetrahydrofuran (10mL) was added 1.0 M lithium aluminum hydride in tetrahydrofuran (1.00mL, 1.00 mmol) dropwise at 0° C. The reaction mixture was stirred atambient temperature for 2 hours, and quenched by the addition of water(0.04 mL), 15% aqueous sodium hydroxide (0.04 mL) and water (0.12 mL).The resulting mixture was stirred for 20 minutes, diluted with ethylacetate, filtered through Celite, and concentrated. The residue wastriturated with dichloromethane to provide the title compound (413 mg,80%). ¹H NMR (500 MHz, DMSO-d₆) δ 11.86 (s, 1H), 7.83 (d, J=1.9 Hz, 1H),7.67 (s, 1H), 7.22 (dd, J=8.2, 1.9 Hz, 1H), 7.13 (s, 1H), 7.11-7.05 (m,1H), 6.96 (d, J=8.1 Hz, 1H), 6.93-6.84 (m, 2H), 5.05-4.98 (m, 1H),4.53-4.42 (m, 2H), 4.36 (s, br, 1H), 3.64 (s, 3H), 2.93 (s, 3H),1.71-1.62 (m, 1H), 1.61-1.54 (m, 1H), 1.50-1.42 (m, 1H), 1.34-1.25 (m,1H). MS (ESI+) m/z 514 (M+H)⁺.

Example 1434-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 142 (31 mg, 0.060 mmol), phenol (8.5 mg, 0.090 mmol) andtriphenylphosphine (23.6 mg, 0.0900 mmol) were combined intetrahydrofuran (0.1 mL) and sonicated for 5 minutes. To this reactionmixture was added diisopropyl azodicarboxylate (0.017 mL, 0.090 mmol)and the mixture was sonicated for 6 hours. The reaction mixture waspartitioned with ethyl acetate and water. The organic layer was washedwith saturated aqueous sodium chloride, dried with anhydrous sodiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 2-4% methanol in dichloromethane). Theresulting material from flash chromatography was triturated with 10%dichloromethane in heptanes to provide the title compound (18 mg, 51%).¹H NMR (500 MHz, DMSO-d₆) δ 11.89 (s, 1H), 7.86 (s, 1H), 7.69 (s, 1H),7.30-7.15 (m, 4H), 7.12-7.04 (m, 1H), 6.99 (d, J=7.9 Hz, 1H), 6.93-6.77(m, 5H), 5.13-5.05 (m, 1H), 4.54-4.42 (m, 2H), 3.89 (s, br, 2H), 3.64(s, 3H), 2.92 (s, 3H), 1.95-1.85 (m, 1H), 1.84-1.71 (m, 2H), 1.49-1.40(m, 1H). MS (ESI+) m/z 590 (M+H)⁺.

Example 144(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

The product from Example 143 was purified by chiral chromatography on aChiralpak IB column, eluting with a 4:6 mixture of methanol/carbondioxide. The fractions containing the first eluted enantiomer werecollected and concentrated. The compound was randomly assigned as the(S)-enantiomer. ¹H NMR (400 MHz, DMSO-d₆) δ 11.88 (s, 1H), 7.86 (d,J=1.7 Hz, 1H), 7.69 (s, 1H), 7.28-7.20 (m, 3H), 7.17 (s, 1H), 7.11-7.04(m, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.92-6.82 (m, 5H), 5.09 (t, J=7.1 Hz,1H), 4.55-4.42 (m, 2H), 3.89 (t, J=6.0 Hz, 2H), 3.65 (s, 3H), 2.92 (s,3H), 1.97-1.85 (m, 1H), 1.83-1.72 (m, 2H), 1.49-1.38 (m, 1H). MS (ESI+)m/z 590 (M+H)⁺.

Example 145(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

The product from Example 143 was purified by chiral chromatography on aChiralpak IB column eluting with a 4:6 mixture of methanol/carbondioxide. The fractions containing the second eluted enantiomer werecollected and concentrated. The compound was randomly assigned as the(R)-enantiomer. ¹H NMR (400 MHz, DMSO-d₆) δ 11.88 (s, 1H), 7.86 (d,J=1.5 Hz, 1H), 7.69 (s, 1H), 7.28-7.20 (m, 3H), 7.17 (s, 1H), 7.11-7.04(m, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.92-6.80 (m, 5H), 5.09 (t, J=7.1 Hz,1H), 4.55-4.42 (m, 2H), 3.89 (t, J=6.0 Hz, 2H), 3.64 (s, 3H), 2.92 (s,3H), 1.95-1.84 (m, 1H), 1.84-1.72 (m, 2H), 1.49-1.39 (m, 1H). MS (ESI+)m/z 590 (M+H)⁺.

Example 1464-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 146a4-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylicacid

Example 146a was prepared according to the procedure used for thepreparation of Example 581, substituting Example 127d for Example 58k,to provide the title compound.

Example 146b4-(4-chlorophenyl)-10-methyl-2-(4-methylpiperazine-1-carbonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To the solution of Example 146a (0.12 g, 0.296 mmol) in anhydrousdichloromethane (5 mL) were added oxalyl chloride (0.052 mL, 0.591 mmol)and dimethylformamide (1.1 μl, 0.015 mmol) and the reaction mixture wasstirred at ambient temperature for 2 hours. The reaction mixture wasconcentrated to dryness and then dried under vacuum for 2 hours. Theresidue was redissolved in dichloromethane (5 mL) and was treated with1-methylpiperazine (0.118 g, 1.183 mmol), and the reaction mixture wasstirred at ambient temperature overnight. The reaction mixture wasconcentrated to give the crude title compound, which was taken into nextreaction without further purification.

Example 146c4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To a solution of Example 146b (100 mg, 0.133 mmol) in anhydroustetrahydrofuran (5 mL) were added BH₃-tetrahydrofuran (1.332 mL, 1.332mmol) and the reaction mixture was stirred at 65° C. for 3 hours. Aftercooling, the reaction mixture was quenched with ethanol (1 mL) and thenconcentrated. 3N HCl (2 mL) was added and the mixture was heated at 78°C. for 4 hours. The reaction mixture was cooled to ambient temperatureand 5 N NaOH (2 mL) was added. The mixture was then extracted withdichlormethane (20 mL×3). The combined organic layers were dried underanhydrous sodium sulfate, filtered, and concentrated. The residue waspurified by reverse phase HPLC (C18, CH₃CN/water (0.01N ammoniumcarbonate), 25-55% gradient) to give the title compound (22 mg, 0.044mmol, 33% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 12.37 (s,1H), 8.50 (s, 1H), 7.69 (d, J=4.2 Hz, 1H), 7.43 (m, 3H), 7.27 (m, 1H),6.92 (d, J=8.8 Hz, 2H), 6.46 (d, J=8.3 Hz, 2H), 6.13 (d, J=15.3 Hz, 1H),4.53 (m, 1H), 3.76 (s, 3H), 3.58 (m, 2H), 1.32 (m, 3H). MS (ESI⁺⁾m/z433.0 (M+H)⁺.

Example 1474-(2,4-difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 147a3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propylmethanesulfonate

Example 142 (103 mg, 0.200 mmol), methanesulfonyl chloride (0.023 mL,0.30 mmol) and triethylamine (0.056 mL, 0.40 mmol) were combined inN,N-dimethylformamide (2 mL). The reaction mixture was stirred atambient temperature for 20 hours. To this reaction mixture was addedmethanesulfonyl chloride (0.023 mL, 0.30 mmol) and triethylamine (0.056mL, 0.40 mmol) and the mixture was stirred at ambient temperature foranother 20 hours. The reaction mixture was partitioned with ethylacetate and water. The organic layer was washed with saturated aqueoussodium chloride, dried with anhydrous sodium sulfate, filtered, andconcentrated to provide the title compound in quantitative yield.

Example 147b4-(2,4-difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 147a (35.5 mg, 0.0600 mmol) and 25% sodium methoxide in methanol(0.027 mL, 0.12 mmol) were combined in tetrahydrofuran (1 mL). Thereaction mixture was heated at 60° C. for 2 hours, cooled, andconcentrated. The residue was purified by flash chromatography (silicagel, 2-4% methanol in dichloromethane) to provide the title compound (10mg, 32%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (d, J=2.2 Hz, 1H), 7.90 (d,J=1.8 Hz, 1H), 7.74 (s, 1H), 7.29 (dd, J=8.2, 1.8 Hz, 1H), 7.20 (d,J=2.6 Hz, 1H), 7.17-7.10 (m, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.97-6.89 (m,2H), 5.07 (t, J=7.3 Hz, 1H), 4.59-4.48 (m, 2H), 3.70 (s, 3H), 3.29 (t,J=6.1 Hz, 2H), 3.19 (s, 3H), 2.99 (s, 3H), 1.82-1.67 (m, 2H), 1.65-1.54(m, 1H), 1.43-1.32 (m, 1H). MS (ESI+) m/z 528 (M+H)⁺.

Example 1484-(2,4-difluorophenyl)-3-(3-ethoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 148 was prepared according to the procedure used for thepreparation of Example 147b, substituting 21% sodium ethoxide in ethanolfor 25% sodium methoxide in methanol, to provide the title compound (16mg, 49%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (d, J=2.4 Hz, 1H), 7.84 (d,J=2.0 Hz, 1H), 7.68 (s, 1H), 7.23 (dd, J=8.2, 2.0 Hz, 1H), 7.14 (d,J=2.7 Hz, 1H), 7.11-7.04 (m, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.90-6.84 (m,2H), 5.08-4.97 (m, 1H), 4.55-4.43 (m, 2H), 3.64 (s, 3H), 3.34-3.25 (m,4H), 2.93 (s, 3H), 1.72-1.60 (m, 2H), 1.58-1.48 (m, 1H), 1.38-1.25 (m,1H), 1.03 (t, J=7.0 Hz, 3H). MS (ESI+) m/z 542 (M+H)⁺.

Example 1494-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 4 mL vial was charged with Example 5f (20 mg, 0.058 mmol),isobutyraldehyde (8.36 mg, 0.116 mmol), acetic acid (0.100 mL, 1.747mmol) and dichloroethane (2.0 mL). The vial was sealed and the mixturewas heated at 80° C. for 1 hour. To this mixture was addedsilica-supported sodiumcyanoborohydride (200 mg, 0.89 mmol/g, 0.178mmol) and the mixture was heated at 80° C. for 4 hours. Upon cooling,the reaction mixture was filtered and concentrated. The residue waspurified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100%gradient) to afford the title compound (16.4 mg, 71%). ¹H NMR (500 MHz,DMSO-d₆) δ 11.80 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.25 (p, J=8.4 Hz,2H), 7.18 (s, 1H), 4.43 (s, 2H), 4.15 (s, 2H), 3.59 (s, 3H), 2.91 (s,3H), 2.76 (d, J=7.1 Hz, 2H), 1.62 (dt, J=13.4, 6.8 Hz, 1H), 0.69 (d,J=6.6 Hz, 6H). MS (ESI+) m/z 400.1 (M+H)⁺.

Example 1504-((1-ethylpiperidin-3-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 150 was prepared according to the procedure used for thepreparation of Example 149, substituting1-ethylpiperidine-3-carbaldehyde for isobutyraldehyde to provide thetitle compound. ¹H NMR (500 MHz, DMSO-d₆) δ 11.85 (s, 1H), 7.66 (d,J=1.7 Hz, 1H), 7.53 (s, 1H), 7.24 (dt, J=17.1, 5.0 Hz, 2H), 7.15 (s,1H), 4.43 (s, 2H), 4.08 (t, J=15.9 Hz, 2H), 3.59 (s, 3H), 3.19 (d,J=54.0 Hz, 2H), 3.06-2.66 (m, 7H), 2.63 (s, 1H), 2.35 (s, 1H), 1.95-1.35(m, 4H), 0.93 (s, 4H). MS (ESI+) m/z 469.1 (M+H)⁺.

Example 15110-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 151 was prepared according to the procedure used for thepreparation of Example 149, substituting dihydro-2H-pyran-4(3H)-one forisobutyraldehyde to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ 11.88 (s, 1H), 7.67 (d, J=1.9 Hz, 1H), 7.58 (s, 1H),7.27-7.17 (m, 3H), 4.48-4.39 (s, 2H), 3.75-4.3 (m, 2H) 3.73-3.64 (m,2H), 3.59 (s, 3H), 3.00 (dd, J=11.7, 2.3 Hz, 2H), 2.90 (s, 3H),2.85-2.77 (m, 1H), 1.80-1.55 (m, 2H), 1.45-1.25 (m, 2H). MS (ESI+) m/z469.1 (M+H)⁺. MS (ESI+) m/z 428.1 (M+H)⁺.

Example 1524-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 152 was prepared according to the procedure used for thepreparation of Example 149, substituting2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde for isobutyraldehyde toprovide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 11.76 (s, 1H),7.65 (d, J=1.8 Hz, 1H), 7.52 (s, 1H), 7.28-7.13 (m, 3H), 4.41 (s, 2H),4.07 (s, 2H), 3.57 (d, J=16.4 Hz, 3H), 3.45 (dd, J=11.3, 4.4 Hz, 1H),3.36 (t, J=11.2 Hz, 1H), 2.90 (s, 3H), 2.83-2.66 (m, 2H), 1.78 (s, 1H),1.39 (dd, J=26.2, 11.8 Hz, 2H), 0.96 (d, J=6.6 Hz, 6H), 0.91-0.47 (m,2H). MS (ESI+) m/z 470.1 (M+H)⁺.

Example 1534-(4-ethoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 153 was prepared according to the procedure used for thepreparation of Example 149, substituting 4-ethoxybutan-2-one forisobutyraldehyde to provide the title compound. ¹H NMR (500 MHz,DMSO-d₆) δ 7.65 (s, 1H), 7.49 (s, 1H), 7.20 (d, J=18.5 Hz, 3H), 4.41 (s,2H), 4.37-4.14 (m, 3H), 3.58 (s, 3H), 3.54-2.95 (m, 4H), 2.90 (s, 3H),1.63 (dd, J=13.6, 6.7 Hz, 1H), 1.51-1.41 (m, 1H), 1.06 (s, 3H), 0.84 (s,3H). MS (ESI+) m/z 444.1 (M+H)⁺.

Example 154N-(2-cyanoethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

A stock solution of Example 141b and diiospropylethyl amine (0.13 M and0.38 M in N,N-dimethylacetamide, respectively, 224 μL, 0.03 mmol3-aminopropanenitrile (1.0 equivalent) and 0.09 mmol diiospropylethylamine (3.0 equivalents)), HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate), (0.2 M in N,N-dimethylacetamide, 224 μL,0.045 mmol, 1.5 equivalents), and 3-aminopropanenitrile (0.40 M inN,N-dimethylacetamide, 113 μL, 0.045 mmol, 1.5 equivalents) wereaspirated from their respective source vials, mixed through aperfluoroalkoxy mixing tube (0.2 mm inner diameter), and loaded into aninjection loop. The reaction segment was injected into the flow reactor(Hastelloy coil, 0.75 mm inner diameter, 1.8 mL internal volume) set at100° C., and passed through the reactor at 180 μL min⁻¹ (10 minuteresidence time). Upon exiting the reactor, the reaction mixture wasloaded directly into an injection loop and purified by preperative HPLC(Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (30 mm×75 mm). A gradientof acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used,at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-7.0 min lineargradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 min linear gradient95-10% A). Samples were injected in 1.5 mL DMSO:methanol (1:1)) toprovide the title compound (12.6 mg, 76% yield). ¹H NMR (400 MHz,DMSO-d₆-D₂O) δ 7.72 (d, J=2.0 Hz, 1H), 7.71 (s, 1H), 7.51-7.67 (m, 1H),7.33 (s, 1H), 7.16 (dd, J=8.2, 2.0 Hz, 1H), 6.98-7.08 (m, 2H), 6.86 (d,J=8.1 Hz, 1H), 5.86 (s, 1H), 4.38-4.51 (m, 2H), 3.67 (s, 3H), 3.14 (ddd,J=13.3, 7.3, 6.0 Hz, 1H), 2.94-3.05 (m, 1H), 2.93 (s, 3H), 1.96-2.16 (m,2H). MS (ESI+) m/z 551.7 (M+H)⁺.

Example 155 methyl2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamido)acetate

Example 155 was prepared according to the procedure used for thepreparation of Example 154, substituting methyl 2-aminoacetate for3-aminopropanenitrile, to provide the title compound (12.7 mg, 74%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.75 (d, J=2.1 Hz, 1H), 7.71 (s,1H), 7.51-7.61 (m, 1H), 7.36 (s, 1H), 7.13 (dd, J=8.3, 2.0 Hz, 1H),6.99-7.09 (m, 2H), 6.83 (d, J=8.2 Hz, 1H), 5.88 (s, 1H), 4.38-4.49 (m,1H), 3.67 (s, 3H), 3.60 (s, 1H), 3.48 (s, 2H), 2.90 (s, 2H). MS (ESI+)m/z 571.0 (M+H)⁺.

Example 1564-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-phenethyl-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 156 was prepared according to the procedure used for thepreparation of Example 154, substituting 2-phenylethanamine for3-aminopropanenitrile, to provide the title compound (15.4 mg, 85%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.75 (d, J=2.1 Hz, 1H), 7.72 (s,1H), 7.63 (d, J=6.4 Hz, 1H), 7.29 (s, 1H), 7.09-7.22 (m, 4H), 6.98-7.10(m, 2H), 6.97 (d, J=1.7 Hz, 2H), 6.93-6.97 (m, 2H), 6.83 (d, J=8.2 Hz,1H), 5.81 (s, 1H), 4.47 (d, J=13.7 Hz, 1H), 4.40 (d, J=13.6 Hz, 1H),3.68 (s, 3H), 3.12 (ddd, J=12.8, 8.8, 5.8 Hz, 1H), 2.87-2.99 (m, 1H),2.81 (s, 3H), 2.32 (ddd, J=13.6, 8.2, 5.6 Hz, 1H), 2.15-2.26 (m, 1H). MS(ESI+) m/z 603.0 (M+H)⁺.

Example 157N-butyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 157 was prepared according to the procedure used for thepreparation of Example 154, substituting butan-1-amine for3-aminopropanenitrile, to provide the title compound (13.8 mg, 83%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.73 (d, J=2.0 Hz, 1H), 7.69 (s,1H), 7.59-7.68 (m, 1H), 7.32 (s, 1H), 7.18-7.12 (m, 2H), 6.98-7.08 (m,2H), 6.85 (d, J=8.1 Hz, 1H), 5.79 (s, 1H), 4.36-4.50 (m, 1H), 3.67 (s,3H), 2.90-3.00 (m, 2H), 2.90 (s, 3H), 2.72 (dd, J=11.6, 4.9 Hz, 1H),0.81-1.02 (m, 4H), 0.66 (t, J=7.1 Hz, 3H). MS (ESI+) m/z 555.1 (M+H)⁺.

Example 158N-cyclohexyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 158 was prepared according to the procedure used for thepreparation of Example 154, substituting cyclohexanamine for3-aminopropanenitrile, to provide the title compound (13.1 mg, 75%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.74 (d, J=2.0 Hz, 1H), 7.71 (s,1H), 7.48-7.58 (m, 1H), 7.32 (s, 1H), 7.16 (dd, J=8.2, 2.0 Hz, 1H),6.97-7.09 (m, 2H), 6.82 (dd, J=25.9, 8.2 Hz, 2H), 5.78 (s, 1H),4.36-4.51 (m, 2H), 3.67 (s, 3H), 3.24-3.36 (m, 1H), 2.87 (s, 3H), 1.85(s, 1H), 1.34-1.55 (m, 4H), 0.86-1.19 (m, 5H), 0.70-0.85 (m, 1H)). MS(ESI+) m/z 581.0 (M+H)⁺.

Example 159N-benzyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 159 was prepared according to the procedure used for thepreparation of Example 154, substituting phenylmethanamine for3-aminopropanenitrile, to provide the title compound (13.2 mg, 75%yield)). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.66-7.80 (m, 3H), 7.36 (s,1H), 7.13-7.17 (m, 1H), 7.11 (m, 3H), 7.09-6.99 (m, 2H), 6.87 (d, J=8.2Hz, 1H), 6.67-6.73 (m, 2H), 5.94 (s, 1H), 4.44-4.57 (m, 2H), 4.27 (d,J=15.3 Hz, 1H), 3.90 (d, J=15.2 Hz, 1H), 3.65 (s, 3H), 2.94 (s, 3H). MS(ESI+) m/z 589.0 (M+H)⁺.

Example 1604-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(3-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 160 was prepared according to the procedure used for thepreparation of Example 154, substituting 3-phenylpropan-1-amine for3-aminopropanenitrile, to provide the title compound (10.77 mg, 58%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.61-7.73 (m, 3H), 7.32 (s, 1H),7.17-7.26 (m, 3H), 7.09-7.17 (m, 2H), 6.97-7.07 (m, 4H), 6.85 (d, J=8.2Hz, 1H), 5.81 (s, 1H), 4.32 (d, J=13.7 Hz, 1H), 4.18-4.26 (m, 1H), 3.67(s, 3H), 2.85-3.03 (m, 1H), 2.79 (s, 3H), 2.65-2.76 (m, 1H), 2.20 (t,J=7.6 Hz, 2H), 1.20-1.34 (m, 2H). MS (ESI+) m/z 617.0 (M+H)⁺.

Example 1614-(2,4-difluorophenyl)-N-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 161 was prepared according to the procedure used for thepreparation of Example 154, substituting 2-methylpropan-1-amine for3-aminopropanenitrile, to provide the title compound (12.7 mg, 76%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.72-7.76 (m, 1H), 7.71 (s, 1H),7.66 (dd, J=15.1, 9.1 Hz, 1H), 7.33 (s, 1H), 7.14 (dd, J=8.2, 2.3 Hz,2H), 6.98-7.09 (m, 2H), 6.84 (d, J=8.2 Hz, 1H), 5.82 (s, 1H), 4.34-4.42(m, 2H), 3.67 (s, 3H), 2.89 (s, 3H), 2.83 (dd, J=12.8, 7.7 Hz, 1H), 1.84(s, 2H), 1.27 (dt, J=13.4, 6.8 Hz, 1H), 0.47 (dd, J=6.6, 1.8 Hz, 6H). MS(ESI+) m/z 555.1 (M+H)⁺.

Example 1624-(2,4-difluorophenyl)-N-(2-hydroxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 162 was prepared according to the procedure used for thepreparation of Example 154, substituting 2-aminoethanol for3-aminopropanenitrile, to provide the title compound (11.7 mg, 72%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.74 (d, J=2.1 Hz, 1H), 7.70 (s,1H), 7.54-7.65 (m, 1H), 7.34 (s, 1H), 7.16 (dd, J=8.2, 2.0 Hz, 1H),6.98-7.08 (m, 2H), 6.85 (d, J=8.2 Hz, 1H), 5.84 (s, 1H), 4.37-4.52 (m,2H), 3.67 (s, 3H), 2.86-3.08 (m, 7H). MS (ESI+) m/z 543.0 (M+H)⁺.

Example 1634-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-N-(oxazol-4-ylmethyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 163 was prepared according to the procedure used for thepreparation of Example 154, substituting oxazol-4-ylmethanamine for3-aminopropanenitrile, to provide the title compound (7.2 mg, 41%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 8.14 (d, J=0.9 Hz, 1H), 7.75 (d,J=2.0 Hz, 1H), 7.70 (s, 1H), 7.57-7.67 (m, 1H), 7.36 (s, 1H), 7.14 (dd,J=8.2, 2.0 Hz, 1H), 6.96-7.10 (m, 3H), 6.85 (d, J=8.2 Hz, 1H), 5.90 (s,1H), 4.38-4.52 (m, 2H), 3.84-4.07 (m, 2H), 3.67 (s, 3H), 2.92 (s, 3H).MS (ESI+) m/z 580.0 (M+H)⁺.

Example 164N-(cyclopropylmethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 164 was prepared according to the procedure used for thepreparation of Example 154, substituting cyclopropylmethanamine for3-aminopropanenitrile, to provide the title compound (13.8 mg, 83%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.74 (d, J=2.1 Hz, 1H), 7.71 (s,1H), 7.54-7.64 (m, 1H), 7.33 (s, 1H), 7.15 (dd, J=8.2, 2.0 Hz, 1H),6.97-7.08 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 5.82 (s, 1H), 4.37-4.50 (m,2H), 3.67 (s, 3H), 2.89 (s, 3H), 2.78-2.87 (m, 1H), 2.60-2.73 (m, 1H),0.42-0.52 (m, 1H), 0.05-0.18 (m, 2H), −0.21-−0.14 (m, 2H). MS (ESI+) m/z553.0 (M+H)⁺.

Example 1654-(2,4-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 165 was prepared according to the procedure used for thepreparation of Example 154, substituting 1-amino-2-methylpropan-2-ol for3-aminopropanenitrile, to provide the title compound (12.2 mg, 71%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.73-7.77 (m, 1H), 7.72 (s, 1H),7.67 (dd, J=12.7, 6.5 Hz, 1H), 7.38 (s, 1H), 7.13 (dd, J=8.2, 2.0 Hz,1H), 6.98-7.10 (m, 2H), 6.83 (d, J=8.2 Hz, 1H), 5.90 (s, 1H), 4.35-4.48(m, 2H), 3.67 (s, 3H), 2.96 (dd, J=13.2, 5.1 Hz, 1H), 2.88 (s, 3H), 2.74(d, J=13.1 Hz, 1H), 0.79 (s, 3H), 0.60 (s, 3H). MS (ESI+) m/z 571.0(M+H)⁺.

Example 1664-(2,4-difluorophenyl)-N-(1-(hydroxymethyl)cyclopropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 166 was prepared according to the procedure used for thepreparation of Example 154, substituting (1-aminocyclopropyl)methanolfor 3-aminopropanenitrile, to provide the title compound (11.5 mg, 68%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.75 (d, J=2.0 Hz, 1H), 7.70 (s,1H), 7.43-7.53 (m, 1H), 7.30 (s, 1H), 7.18 (dd, J=8.2, 2.0 Hz, 1H),6.94-7.08 (m, 2H), 6.87 (d, J=8.1 Hz, 1H), 5.77 (s, 1H), 4.36-4.53 (m,2H), 3.66 (s, 3H), 3.26 (d, J=11.1 Hz, 1H), 3.08 (d, J=11.1 Hz, 1H),2.90 (s, 3H), 0.40-0.53 (m, 2H), −0.03-0.13 (m, 2H). MS (ESI+) m/z 569.0(M+H)⁺.

Example 1674-(2,4-difluorophenyl)-10-methyl-N-(1-methylcyclopropyl)-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 167 was prepared according to the procedure used for thepreparation of Example 154, substituting 1-methylcyclopropanamine for3-aminopropanenitrile, to provide the title compound (10.8 mg, 65%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.75 (d, J=2.1 Hz, 1H), 7.70 (s,1H), 7.50 (d, J=7.3 Hz, 1H), 7.28 (s, 1H), 7.18 (dd, J=8.2, 2.0 Hz, 1H),6.94-7.08 (m, 2H), 6.88 (d, J=8.1 Hz, 1H), 5.73 (s, 1H), 4.36-4.52 (m,2H), 3.66 (s, 3H), 2.88 (s, 3H), 0.93 (s, 3H), 0.23-0.34 (m, 2H),0.13-0.18 (m, 2H). MS (ESI+) m/z 553.0 (M+H)⁺.

Example 1684-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(4-phenylbutyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide

Example 168 was prepared according to the procedure used for thepreparation of Example 154, substituting 4-phenylbutan-1-amine for3-aminopropanenitrile, to provide the title compound (14.7 mg, 77%yield). ¹H NMR (400 MHz, DMSO-d₆-D₂O) δ 7.70-7.72 (m, 1H), 7.69 (s, 1H),7.57-7.67 (m, 1H), 7.32 (s, 1H), 7.20-7.27 (m, 2H), 6.98-7.19 (m, 6H),6.84 (d, J=8.2 Hz, 1H), 5.80 (s, 1H), 4.32-4.44 (m, 2H), 3.67 (s, 3H),2.97 (dt, J=13.2, 6.6 Hz, 1H), 2.87 (s, 3H), 2.68-2.81 (m, 1H), 2.37 (t,J=7.5 Hz, 2H), 1.11-1.25 (m, 2H), 0.96-1.11 (m, 2H). MS (ESI+) m/z 630.9(M+H)⁺.

Example 1694-(3,3-dimethylbutanoyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

The product from Example 42c (0.0 5 g, 0.174 mmol), tert-butylacetylchloride (0.028 g, 0.209 mmol), N,N-dimethylpyridin-4-amine (2.126 mg,0.017 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.152 mL, 0.870 mmol)were combined in dimethylacetamide (0.870 mL) and stirred at 50° C. for18 hours. The reaction mixture was cooled to ambient temperature andpartitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, filtered and concentrated. Purification by reverse phaseHPLC (C18, CH₃CN/0.1% TFA in water, 10-100% gradient) afforded the titlecompound (0.012 g, 18%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (s, 1H), 7.83(s, 1H), 7.53 (d, J=10.38 Hz, 1H), 7.18-7.26 (m, 2H), 5.59 (d, J=14.65Hz, 1H), 3.87 (d, J=14.95 Hz, 1H), 3.60 (s, 3H), 1.79-1.92 (m, 2H), 0.70(s, 9H). MS (ESI+) m/z 386 (M+H)⁺.

Example 170 tert-butyl((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamateExample 170a tert-butyl(trans-4-((2-bromo-4-(methylsulfonyl)phenyl)amino)cyclohexyl)carbamate

A mixture of 2-bromo-1-fluoro-4-(methylsulfonyl)benzene (0.403 g, 1.592mmol) and tert-butyl (trans-4-aminocyclohexyl)carbamate (0.352 g, 1.592mmol) in dimethylsulfoxide (12 mL) and N,N-diisopropylethylamine (0.32mL, 1.831 mmol) was heated at 100° C. for 4 hours. The reaction mixturewas cooled to ambient temperature and partitioned between aqueousammonium chloride solution and diethyl ether. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was purifiedby flash column chromatography on silica gel, eluting with 25% ethylacetate in hexanes to afford the title compound (0.390 g, 0.872 mmol,55% yield).

Example 170b tert-butyl((trans)-4-((2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-(methylsulfonyl)phenyl)amino)cyclohexyl)carbamate

A mixture of Example 170a (0.380 g, 0.849 mmol), Example 1f (0.382 g,0.892 mmol), cesium fluoride (0.387 g, 2.550 mmol) andtetrakis(triphenylphosphine)palladium (0.098 g, 0.085 mmol) indimethoxyethane (20 mL) and methanol (10 mL) was stirred under an argonatmosphere at 80° C. for 2 hours. The reaction mixture was cooled toambient temperature and excess 5N sodium hydroxide solution (8 mL) wasadded. The reaction mixture was stirred at ambient temperature for 2hours and then partitioned between aqueous ammonium chloride solutionand ethyl acetate. The aqueous layer was extracted with additional ethylacetate twice. The combined organic layers were washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered and concentrated. The residue was purified by flash columnchromatography on silica gel, eluting with 2% methanol indichloromethane to afford the title compound (0.279 g, 0.543 mmol, 64%yield).

Example 170c tert-butyl((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

To a stirring mixture of Example 170b (0.048 g, 0.093 mmol) andparaformaldehyde (0.048 g, 1.599 mmol) in tetrahydrofuran (1.0 mL) atambient temperature was added 1M solution of titanium tetrachloride intoluene (0.187 mL, 0.187 mmol). The reaction mixture suspension wasstirred at ambient temperature for 1 hour and then partitioned betweenethyl acetate and saturated sodium bicarbonate. The aqueous layer wasextracted three times with ethyl acetate. The combined organic layerswere washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100% gradient) togive the title compound (0.0043 g, 9% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 11.83 (s, 1H), 8.13 (s, 1H), 7.73-7.62 (m, 2H), 7.36 (d, J=8.5 Hz,1H), 7.20-7.14 (m, 1H), 6.62 (d, J=7.7 Hz, 1H), 4.18 (s, 2H), 3.64 (s,3H), 3.26 (s, 3H), 3.22-3.14 (m, 1H), 3.02-2.93 (m, 1H), 1.83-1.55 (m,4H), 1.52-1.25 (m, 11H), 1.16-0.95 (m, 2H). MS (ESI+) m/z 527.1 (M+H)⁺.

Example 1714-((trans)-4-aminocyclohexyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 170c (0.0114 g, 0.022 mmol) in dichloromethane (1 mL) wastreated with trifluoroacetic acid (0.20 mL) and stirred at ambienttemperature for 1 hour. The reaction mixture was concentrated and driedunder vacuum to afford the title compound as the trifluoracetic acidsalt (0.0113 g, 97% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (d, J=2.2Hz, 1H), 8.14 (d, J=2.2 Hz, 1H), 7.68 (dd, J=8.5, 2.3 Hz, 4H), 7.37 (d,J=8.5 Hz, 1H), 7.15 (d, J=2.5 Hz, 1H), 4.12 (bs, 2H), 3.64 (s, 3H), 3.26(s, 3H), 3.09-2.90 (m, 2H), 1.87 (d, J=10.6 Hz, 2H), 1.72 (d, J=12.6 Hz,2H), 1.47 (dd, J=23.8, 11.1 Hz, 2H), 1.29-1.18 (m, 2H). MS (ESI+) m/z427.1 (M+H)⁺.

Example 1724-(cyclopropylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 172 was prepared according to the procedure used for thepreparation of Example 74, substituting cyclopropanesulfonyl chloridefor 4-methylbenzene-1-sulfonyl chloride to provide the title compound.¹H NMR (400 MHz, DMSO-d₆/D₂O) δ 7.84 (d, J=2.0 Hz, 1H), 7.75 (s, 1H),7.44 (d, J=8.1 Hz, 1H), 7.40-7.35 (m, 1H), 7.32 (s, 1H), 5.12 (d, J=16.7Hz, 1H), 4.54 (dt, J=30.5, 15.1 Hz, 3H), 3.64 (s, 3H), 2.99 (s, 3H),1.76-1.64 (m, 1H), 0.49 (d, J=5.1 Hz, 3H), 0.35-0.24 (m, 1H). MS (APCI+)m/z 448.0 (M+H)⁺.

Example 173 ethyl5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylateExample 173a tert-butyl5,7-difluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-1-carboxylate

The product from Example 42c (0.86 g, 2.99 mmol), di-tert-butyldicarbonate (0.98 g, 4.49 mmol), N,N-dimethylpyridin-4-amine (0.018 g,0.150 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.569 mL, 8.98 mmol)were combined in dimethylacetamide (11.98 mL) and stirred at 50° C. for1 hour. The reaction mixture was cooled to ambient temperature andpartitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydroussodium sulfate, filtered, and concentrated to afford the title compound(1.0 g, 86%).

Example 173b 1-tert-butyl 4-ethyl 5,7-difluoro-10-methyl-11l-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-1,4(3H)-dicarboxylate

The product from Example 173a (0.7 g, 1.807 mmol), ethylcarbonochloridate (0.7 g, 6.45 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (1.0 g, 2.63 mmol) andN-ethyl-N-isopropylpropan-2-amine (1.6 mL, 9.16 mmol) were combined indimethylacetamide (9 mL) and stirred at 50° C. for 2 hours. The reactionmixture was cooled to ambient temperature and partitioned between ethylacetate and water. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, filtered, andconcentrated. Purification by chromatography (silica gel, 0-60% ethylacetate in heptanes) afforded the title compound (0.57 g, 69%).

Example 173c ethyl5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate

The product from Example 173b (0.57 g, 1.241 mmol) in dichloromethane (5mL)/TFA (5 mL) was stirred at ambient temperature for 1 hour,concentrated, and azeotroped 3× with dichloromethane. Purification bytrituration in a minimal volume of 9:1 dichloromethane/methanol affordedthe title compound (0.427 g. 96%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (s,1H), 7.90 (s, 1H), 7.53 (dd, J=10.68, 1.53 Hz, 1H), 7.25-7.33 (m, 2H),5.25 (d, J=15.56 Hz, 1H), 4.13 (d, J=15.56 Hz, 1H), 3.99-4.06 (m, 1H),3.74-3.84 (m, 1H), 3.61 (s, 3H), 0.99 (t, J=7.17 Hz, 3H). MS (ESI+) m/z360 (M+H)⁺.

Example 1744-(2,4-difluorophenyl)-10-methyl-3-(3-(methylamino)propyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 147a (35.5 mg, 0.0600 mmol), 2.0 M methanamine intetrahydrofuran (0.150 mL, 0.300 mmol) and potassium carbonate (24.9 mg,0.180 mmol) were combined in tetrahydrofuran (1 mL). The reactionmixture was heated at 60° C. for 2 hours, cooled, and concentrated. Theresidue was purified by reverse phase HPLC (C18, CH₃CN/water (10 mMammonium acetate), 20-100% gradient) to provide the title compound (19mg, 60%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (d, J=1.8 Hz, 1H), 7.68 (s,1H), 7.23 (dd, J=8.2, 1.8 Hz, 1H), 7.14 (s, 1H), 7.13-7.04 (m, 1H), 6.97(d, J=8.2 Hz, 1H), 6.93-6.82 (m, 2H), 5.05-4.97 (m, 1H), 4.56-4.42 (m,2H), 3.64 (s, 3H), 2.92 (s, 3H), 2.45 (t, J=6.1 Hz, 2H), 2.22 (s, 3H),1.72-1.58 (m, 2H), 1.54-1.42 (m, 1H), 1.36-1.24 (m, 1H). MS (ESI+) m/z527 (M+H)⁺.

Example 1754-(2,4-difluorophenyl)-3-(3-(dimethylamino)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-1(10H)-one

Example 175 was prepared according to the procedure used for thepreparation of Example 174, substituting 2.0 M dimethylamine intetrahydrofuran for 2.0 M methanamine in tetrahydrofuran, to provide thetitle compound (20 mg, 62%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (s, 1H),7.84 (d, J=1.8 Hz, 1H), 7.67 (s, 1H), 7.22 (dd, J=8.2, 1.7 Hz, 1H), 7.14(s, 1H), 7.10-7.05 (m, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.93-6.83 (m, 2H),5.01 (t, J=7.4 Hz, 1H), 4.53-4.42 (m, 2H), 3.64 (s, 3H), 2.92 (s, 3H),2.21-2.03 (m, 2H), 2.01 (s, 6H), 1.72-1.60 (m, 1H), 1.59-1.53 (m, 1H),1.51-1.41 (m, 1H), 1.32-1.22 (m, 1H). MS (ESI+) m/z 541 (M+H)⁺.

Example 1764-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To the solution of Example 60 (110 mg, 0.190 mmol) in anhydroustetrahydrofuran (5 mL) was added BH₃.THF (1.896 mL, 1.896 mmol) and thereaction mixture was stirred at 65° C. for 18 hours. The reactionmixture was quenched with ethanol (1 mL), followed by the addition ofHCl (3 M, 2 mL). The mixture was stirred at 70° C. for an additional 4hours. The solvent was evaporated and the residue was treated with 5 NNaOH (2 mL) and the mixture was extracted with dichlorormethane (20mL×3). The combined organic layers were concentrated and the residue waspurified by HPLC (C18, 30%-40% acetonitrile in 0.1% aqueous ammoniumhydroxide) to provide the title compound (15 mg, 0.026 mmol, 14% yield).¹H NMR (400 MHz, DMSO-d₆) δ 11.87 (s, 1H), 7.89 (s, 1H), 7.60 (s, 1H),7.46 (d, J=7.9 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H),6.43 (d, J=8.9 Hz, 2H), 5.22-5.18 (m, 1H), 4.66-4.34 (m, 3H), 3.79-3.73(m, 1H), 3.66-3.60 (m, 1H), 3.54 (s, 3H), 3.00 (s, 3H), 2.47-2.27 (m,8H), 2.17 (s, 3H). MS (ESI+) m/z 566.2 (M+H)⁺.

Example 1772-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-7-yl)acetonitrileExample 177a 2-(4-amino-3-bromophenyl)acetonitrile

To a solution of 2-(4-aminophenyl)acetonitrile (3.0 g, 22.70 mmol) in 40mL dimethylformamide cooled with ice bath was added N-bromosuccinimide(4.04 g, 22.70 mmol) in portions. The mixture was stirred at 0° C. for30 minutes and then at ambient temperature for 1 hour. Water was added.The precipitate was collected by filtration, washed with water, anddried in a vacuum oven at 40° C. to give the title compound (3.56 g,16.9 mmol, 74.4% yield).

Example 177b2-(4-amino-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)acetonitrile

A mixture of Example 177a (0.739 g, 3.50 mmol), Example 1f (1.5 g, 3.50mmol), tris(dibenzylideneacetone)dipalladium(0) (0.080 g, 0.088 mmol),1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.051 g,0.175 mmol) and potassium phosphate (2.230 g, 10.51 mmol) in 30 mLdioxane and 10 mL water was heated at 80° C. under nitrogen for 2 hours.Water was added, and the mixture was extracted with ethyl acetate (3×),washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, and filtered. The filtrate was concentrated andpurified by column chromatography (silica gel, 0-40% ethylacetate/heptanes gradient) to give the title compound (0.933 g, 2.157mmol, 61.6% yield).

Example 177c{4-[(4-fluorophenyl)amino]-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl}acetonitrile

A mixture of Example 177b (120 mg, 0.277 mmol), 1-bromo-4-fluorobenzene(48.6 mg, 0.277 mmol), cesium carbonate (226 mg, 0.694 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-phos)(13.23 mg, 0.028 mmol) in 4 mL toluene and 1 mL tert-butanol was heatedin a Biotage initiator microwave oven at 150° C. for 40 minutes.Thereaction mixture was then concentrated. The residue was treated with 1mL 4N aqueous NaOH solution and 3 mL dioxane. The resulting mixture washeated at 80° C. in the microwave oven for 20 minutes. Water was added,and the mixture was extracted with ethyl acetate (3×), washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was concentrated and the residue waspurified by column chromatography (silica gel, 0-10%methanol/dichloromethane gradient) to afford the title compound (43 mg,0.115 mmol, 41.6% yield).

Example 177d2-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-7-yl)acetonitrile

To a mixture of Example 177c (36 mg, 0.097 mmol) and paraformaldehyde(43.5 mg, 1.450 mmol) in 2 mL tetrahydrofuran was added titanium(IV)chloride (193 μL, 0.193 mmol, 1.0 M toluene solution). The dark redmixture was stirred at ambient temperature for 3 hours. The mixture wascooled with an ice bath and quenched with water, extracted with ethylacetate (2×), washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, and filtered. The filtrate was concentratedand the residue was purified by column chromatography (silica gel, 0-10%methanol/dichloromethane gradient) to give the title compound (12 mg,0.031 mmol, 32% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.62-11.28 (m, 1H),7.82 (d, J=1.7 Hz, 1H), 7.58 (s, 1H), 7.36 (dd, J=8.0, 1.9 Hz, 1H),7.32-7.26 (m, 2H), 6.79-6.71 (m, 2H), 6.47-6.34 (m, 2H), 4.85-4.62 (m,2H), 4.05 (s, 2H), 3.56 (s, 3H). MS (ESI+) m/z 385.2 (M+H)⁺.

Example 1784-(2,2-dimethyl-3-(pyrrolidin-1-yl)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 178 was prepared according to the procedure used for thepreparation of Example 149, substituting2,2-dimethyl-3-(pyrrolidin-1-yl)propanal for isobutyraldehyde to providethe title compound as the trifluoroacetic acid salt. ¹H NMR (400 MHz,pyridine-d₅) δ 13.69-12.65 (m, 1H), 8.08 (dd, J=10.0, 2.0 Hz, 1H), 7.57(d, J=3.6 Hz, 2H), 7.42-7.31 (m, 2H), 4.78 (s, 2H), 4.34 (s, 2H), 3.64(s, 3H), 3.13 (s, 3H), 3.09 (s, 2H), 3.02 (s, 2H), 2.20-2.85 (m, 4H)1.83-1.68 (m, 4H), 0.99 (s, 6H). MS (ESI+) m/z 483.1 (M+H)⁺.

Example 1792-(3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)pyrrolidin-1-yl)aceticacid

Example 179 was prepared according to the procedure used for thepreparation of Example 149, substituting 2-(3-oxopyrrolidin-1-yl)aceticacid for isobutyraldehyde to provide the title compound as thetrifluoroacetic acid salt. ¹H NMR (400 MHz, pyridine-d₅) δ 13.47-13.38(m, 1H), 8.10-8.01 (m, 1H), 7.57-7.48 (m, 2H), 7.47-7.29 (m, 2H), 4.73(s, 2H), 4.39-3.77 (m, 4H), 3.64 (s, 3H), 3.58-3.16 (m, 4H), 3.12 (d,J=6.6 Hz, 3H), 2.50 (s, 1H), 2.22-2.03 (m, 2H), 1.37-1.22 (m, 1H). MS(APCI+) m/z 471.1 (M+H)⁺.

Example 18010-methyl-7-((methylsulfonyl)methyl)-4-(2-methyltetrahydrofuran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 180 was prepared according to the procedure used for thepreparation of Example 149, substituting 2-methyldihydrofuran-3(2H)-onefor isobutyraldehyde to provide the title compound. ¹H NMR (400 MHz,pyridine-d₅) δ 13.49-13.40 (m, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.60 (dd,J=8.4, 1.9 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.45-7.27 (m, 2H), 4.82-4.68(m, 2H), 4.68-3.92 (m, 5H), 3.86-3.40 (m, 4H), 3.12 (s, 3H), 2.25-1.85(m, 2H), 1.36-1.14 (m, 3H). MS (APCI+) m/z 428.1 (M+H)⁺.

Example 18110-methyl-4-(1-methylpiperidin-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 181 was prepared according to the procedure used for thepreparation of Example 149, substituting 1-methylpiperidin-4-one forisobutyraldehyde to provide the title compound as the trifluoroaceticacid salt. ¹H NMR (400 MHz, pyridine-d₅) δ 14.00-13.44 (m, 1H),8.17-7.99 (m, 1H), 7.58-7.42 (m, 2H), 7.42-7.28 (m, 2H), 4.89-4.71 (m,2H), 4.67-4.11 (m, 3H), 3.65 (s, 3H), 3.53-3.30 (m, 2H), 3.18-3.10 (m,3H), 2.90-2.6 (m, 2H), 2.69 (s, 3H), 2.27-1.52 (m, 4H). MS (APCI+) m/z441.1 (M+H)⁺.

Example 18210-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 182 was prepared according to the procedure used for thepreparation of Example 149, substituting dihydro-2H-pyran-3(4H)-one forisobutyraldehyde to provide the title compound. ¹H NMR (400 MHz,pyridine-d₅) δ 13.52-13.29 (m, 1H), 8.09-8.01 (m, 1H), 7.55 (d, J=7.6Hz, 2H), 7.52-7.28 (m, 2H), 4.84-4.69 (m, 2H), 4.60-3.66 (m, 4H),3.65-3.56 (m, 3H), 3.53-3.16 (m, 2H), 3.16-3.03 (m, 2H), 2.72-2.56 (m,1H), 2.21-1.19 (m, 5H). MS (APCI+) m/z 428.1 (M+H)⁺.

Example 1834-((1-isopropylpiperidin-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 183 was prepared according to the procedure used for thepreparation of Example 149, substituting1-isopropylpiperidine-4-carbaldehyde for isobutyraldehyde to provide thetitle compound as the trifluoroacetic acid salt. ¹H NMR (400 MHz,pyridine-d₅) δ 13.69-12.65 (m, 1H), 8.08 (dd, J=10.0, 2.0 Hz, 1H), 7.57(d, J=3.6 Hz, 2H), 7.42-7.31 (m, 2H), 4.81-4.71 (m, 2H), 4.30-4.19 (m,2H), 3.64 (d, J=6.9 Hz, 3H), 3.54-3.19 (m, 4H), 3.21 (s, 3H), 3.06-2.88(m, 2H), 2.78-2.53 (m, 2H), 1.97 (dddd, J=9.6, 8.6, 5.4, 2.1 Hz, 2H),1.84-1.75 (m, 2H), 1.18-1.02 (m, 6H). MS (APCI+) m/z 483.1 (M+H)⁺.

Example 18410-methyl-7-((methylsulfonyl)methyl)-4-(1-(2-oxotetrahydrofuran-3-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 184 was prepared according to the procedure used for thepreparation of Example 149, substituting 3-acetyldihydrofuran-2(3H)-onefor isobutyraldehyde to provide the title compound. ¹H NMR (400 MHz,pyridine-d₅) δ 13.48-13.34 (m, 1H), 8.10-8.01 (m, J=2.1 Hz, 1H),7.61-7.53 (m, 2H), 7.50-7.31 (m, 2H), 4.80-4.67 (m, 2H), 4.40-3.98 (m,4H), 3.62 (s, 3H), 3.10 (s, 3H), 2.80-2.60 (m, 1H), 2.46 (s, 3H),2.18-1.77 (m, 3H). MS (APCI+) m/z 456.1 (M+H)⁺.

Example 1854-(1-methoxypropan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 185 was prepared according to the procedure used for thepreparation of Example 149, substituting 1-methoxypropan-2-one forisobutyraldehyde to provide the title compound. ¹H NMR (400 MHz,pyridine-d₅) δ 13.89-12.95 (m, 1H), 8.05 (d, J=1.3 Hz, 1H), 7.56-7.44(m, 3H), 7.44-7.34 (m, 1H), 4.71 (d, J=12.4 Hz, 2H), 4.63-4.06 (m, 2H),3.73-3.64 (m, 1H), 3.64-3.56 (m, 3H), 3.56-3.42 (m, 1H), 3.40-3.27 (m,1H), 3.17 (s, 3H), 3.09 (d, J=5.1 Hz, 3H), 1.27-1.12 (m, 3H). MS (APCI+)m/z 416.0 (M+H)⁺.

Example 1864-(4-methoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 186 was prepared according to the procedure used for thepreparation of Example 149, substituting 4-methoxybutan-2-one forisobutyraldehyde to provide the title compound. ¹H NMR (400 MHz,pyridine-d₅) δ 13.63-13.11 (m, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.57-7.36(m, 4H), 4.88-4.51 (m, 2H), 4.51-3.96 (m, 2H), 3.86-3.72 (m, 1H), 3.62(s, 3H), 3.47-3.34 (m, 1H), 3.33-3.20 (m, 1H), 3.17-2.99 (m, 6H),2.06-1.87 (m, 1H), 1.80-1.62 (m, 1H), 1.31-1.05 (m, 3H). MS (APCI+) m/z430.0 (M+H)⁺.

Example 18710-methyl-4-(1-methylpyrrolidin-3-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 187 was prepared according to the procedure used for thepreparation of Example 149, substituting 1-methylpyrrolidin-3-one forisobutyraldehyde to provide the title compound as the trifluoroaceticacid salt. ¹H NMR (400 MHz, pyridine-d₅) δ 13.57-13.33 (m, 1H), 8.05 (d,J=1.9 Hz, 1H), 7.57-7.52 (m, 2H), 7.51-7.29 (m, 2H), 4.81-4.69 (m, 2H),4.69-4.06 (m, 3H), 3.67 (s, 3H), 3.62-3.16 (m, 4H), 3.13 (s, 3H),2.92-2.74 (m, 3H), 2.35-1.91 (m, 2H). MS (APCI+) m/z 427.1 (M+H)⁺.

Example 18810-methyl-7-((methylsulfonyl)methyl)-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 188 was prepared according to the procedure used for thepreparation of Example 149, substituting1-(tetrahydro-2H-pyran-4-yl)ethanone for isobutyraldehyde to provide thetitle compound. ¹H NMR (400 MHz, pyridine-d₅) δ 13.48-13.34 (m, 1H),8.11-8.02 (m, 1H), 7.67-7.59 (m, 1H), 7.51-7.40 (m, 2H), 7.39-7.29 (m,1H), 4.90-4.63 (m, 2H), 4.54-3.64 (m, 4H), 3.61 (s, 3H), 3.51-3.15 (m,3H), 3.11 (s, 3H), 1.83-1.44 (m, 4H), 1.38-1.01 (m, 4H). MS (APCI+) m/z456.1 (M+H)⁺.

Example 18910-methyl-4-(1-methylazepan-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 189 was prepared according to the procedure used for thepreparation of Example 149, substituting 1-methylazepan-4-one forisobutyraldehyde to provide the title compound as the trifluoroaceticacid salt. ¹H NMR (400 MHz, pyridine-d₅) δ 13.83-13.26 (m, 1H), 8.07(dd, J=18.6, 1.9 Hz, 1H), 7.55 (d, J=2.5 Hz, 1H), 7.50-7.27 (m, 3H),4.82-4.73 (m, 1H), 4.66 (s, 2H), 4.54-4.45 (m, 2H), 3.62 (s, 3H),3.59-3.20 (m, 4H), 3.06 (s, 3H), 2.80 (s, 3H), 2.39-1.46 (m, 6H). MS(APCI+) m/z 455.2 (M+H)⁺.

Example 1904-(1-ethylpiperidin-3-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 190 was prepared according to the procedure used for thepreparation of Example 149, substituting 1-ethylpiperidin-3-one forisobutyraldehyde to provide the title compound as the trifluoroaceticacid salt. ¹H NMR (400 MHz, pyridine-d₅) δ 13.83-12.95 (m, 1H),8.08-8.00 (m, 1H), 7.75-7.69 (m, 1H), 7.56 (s, 1H), 7.49-7.35 (m, 2H),4.84-4.58 (m, 2H), 4.65-3.76 (m, 3H), 3.69 (s, 3H), 3.47-3.19 (s, 2H),3.20-3.14 (m, 3H), 3.11-2.55 (m, 4H), 2.40-1.58 (m, 4H), 1.16-1.02 (m,3H). MS (APCI+) m/z 455.0 (M+H)⁺.

Example 19110-methyl-7-((methylsulfonyl)methyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 191 was prepared according to the procedure used for thepreparation of Example 149, substituting2-(tetrahydro-2H-pyran-4-yl)acetaldehyde for isobutyraldehyde to providethe title compound. ¹H NMR (400 MHz, pyridine-d₅) δ 13.45-13.38 (m, 1H),8.08 (d, J=2.0 Hz, 1H), 7.66-7.60 (m, 1H), 7.56 (s, 1H), 7.50-7.37 (m,2H), 4.74 (s, 2H), 4.33 (s, 2H), 3.91-3.78 (m, 2H), 3.63 (s, 3H),3.29-3.13 (m, 4H), 3.11 (s, 3H), 1.56-1.28 (m, 5H), 1.26-1.07 (m, 2H).MS (APCI+) m/z 456.1 (M+H)⁺.

Example 1924-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)benzonitrileExample 192a 4-((4-((methylsulfonyl)methyl)phenyl)amino)benzonitrile

A 20 mL microwave vial was charged with 4-aminobenzonitrile (0.121 g,1.023 mmol), Example 9a (0.2549 g, 1.023 mmol), diacetoxypalladium (9.19mg, 0.041 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.039g, 0.082 mmol), cesium carbonate (0.467 g, 1.432 mmol), toluene (8.5 mL)and t-butanol (1.7 mL) to give a yellow suspension. The tube was sealed,and the reaction mixture was heated in a Biotage Creator at 150° C. for15 minutes fixed hold time. The reaction mixture was filtered through a2 g Celite SPE column and rinsed with ethyl acetate. The filtrate waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash chromatography (20-100% ethyl acetate/heptanes) to provide thetitle compound (0.100 g, 34% yield).

Example 192b4-((2-bromo-4-((methylsulfonyl)methyl)phenyl)amino)benzonitrile

In a 250 mL round-bottomed flask was placed Example 192a (0.100 g, 0.349mmol) in acetic acid (3.49 mL) to give a white suspension.N-bromosuccinimide (0.062 g, 0.349 mmol) was added in 2 portions 10minutes apart. After the 1st portion of N-bromosucinimide was added, 3mL dimethylformamide were added. The reaction mixture was stirred atambient temperature for 4 hours. The reaction mixture was quenched with30 mL 10% sodium thiosulfate and diluted with water. The reactionmixture was extracted 2× with ethyl acetate. The combined organic layerswere washed 2× with 2N NaOH (until the pH of the aqueous was >7) and 1×with saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography (50-100% ethyl acetate/heptanes) to provide the titlecompound as a white solid (0.1007 g, 79% yield).

Example 192c4-((2-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((methylsulfonyl)methyl)phenyl)amino)benzonitrile

Example 192c was prepared according to the procedure used for thepreparation of Example 6b, substituting Example 192b for Example 6a, toprovide the title compound as a white solid (0.115 g, 78% yield).

Example 192d4-((2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((methylsulfonyl)methyl)phenyl)amino)benzonitrile

Example 192d was prepared according to the procedure used for thepreparation of Example 12d, substituting Example 192c for Example 12c,to provide the title compound (0.0575 g, 68% yield).

Example 192e4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)benzonitrile

Example 192e was prepared according to the procedure used for thepreparation of Example 82, substituting Example 192d for Example 12d,and paraformaldehyde for methyl 4-oxobutanoate to provide the titlecompound (0.0277 g, 47% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.88-11.93(m, 1H), 7.95 (d, J=1.9 Hz, 1H), 7.64 (s, 1H), 7.48 (dd, J=8.0, 1.9 Hz,1H), 7.34-7.46 (m, 4H), 6.48-6.58 (m, 2H), 5.28 (d, J=16.3 Hz, 1H),4.71-4.42 (m, 3H), 3.56 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 445.2(M+H)⁺.

Example 1934-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinomethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 193a4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholine-4-carbonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 193a was prepared according to the procedure used for thepreparation of Example 58m, substituting morpholine for ammoniumhydroxide (25% wt/wt in water), to provide the title compound.

Example 193b4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinomethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 193b was prepared according to the procedure used for thepreparation of Example 146c, substituting Example 193a for Example 146b,to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (s,1H), 7.89 (s, 1H), 7.60 (s, 1H), 7.49-7.41 (m, 1H), 7.34 (d, J=8.0 Hz,1H), 6.96 (d, J=9.0 Hz, 2H), 6.42 (d, J=9.0 Hz, 2H), 5.24-5.20 (m, 1H),4.61-4.38 (m, 3H), 3.80-3.71 (m, 1H), 3.69-3.57 (m, 5H), 3.54 (s, 3H),3.00 (s, 3H), 2.46-2.36 (m, 4H). MS (ESI+) m/z 553.2 (M+H)⁺.

Example 194N-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamideExample 194a2-bromo-N-(4-fluorophenyl)-4-((methylsulfonyl)methyl)aniline

A 100 mL flask was charged with Example 58g (2 g, 7.57 mmol),1-fluoro-4-iodobenzene (3.36 g, 15.14 mmol), palladium(II) acetate(0.085 g, 0.379 mmol), xantphos (0.219 g, 0.379 mmol), Cs₂CO₃ (2.52 g,7.72 mmol) and anhydrous dioxane (40 mL) under argon at roomtemperature. The mixture was heated at 110° C. for 18 hours. Aftercooling, the reaction mixture was filtered through a pad of Celite andwashed with ethyl acetate. The solvent was removed and the residue waspurified by silica gel chromatography, eluting with a gradient of 10/1to 2/1 petroleum ether/ethyl acetate to provide the title compound (1.1g, 2.9 mmol, 39% yield) as yellow solid.

Example 194b ethyl1-benzyl-4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 58f (0.8 g, 1.192 mmol), Example 194a (0.498 g,1.251 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.035 g,0.119 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.055 g, 0.060mmol) and K₃PO₄ (0.632 g, 2.98 mmol) were combined and sparged withargon for 30 minutes. A solution of 1,4-dioxane (10 mL) and water (2.500mL) was sparged with nitrogen for 30 minutes and transferred by syringeinto the reaction vessel under argon. The reaction mixture was stirredat 60° C. for 4 hours. The mixture was treated with ethyl acetate (150mL) and water (50 mL) and the undissolved solid was filtered and washedwith ethyl acetate several times. The resulting solid was dried undervacuum to afford the title compound (0.58 g, 0.711 mmol, 59.6% yield).

Example 194c ethyl4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of Example 194b (0.58 g, 0.987 mmol), anisole (0.216 mL, 1.974mmol) and concentrated H₂SO₄ (0.5 mL, 9.38 mmol) in TFA (10 mL, 130mmol) was heated at 90° C. for 6 hours. Excess TFA was removed underreduced pressure, and the residue was partitioned between water (10 mL)and ethyl acetate (50 mL). The organic layer was separated, and theaqueous layer was extracted with additional ethyl acetate twice (20 mL).The combined organic layers were washed with saturated aqueous sodiumbicarbonate (10 mL), followed by saturated aqueous sodium chloride, (10mL), dried over anhydrous magnesium sulfate, filtered, and concentratedto give the title compound (0.24 g, 0.241 mmol, 24.4% yield).

Example 194d ethyl4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate

A mixture of Example 194c (0.31 g, 0.623 mmol), HCl (4 M in dioxane) (4mL, 16.00 mmol) and paraformaldehyde (0.374 g, 12.46 mmol) in methanol(2.5 mL) was heated at 130° C. for 1.5 hours under microwave. Thesolvent was removed under reduced pressure to provide the titlecompound.

Example 194eN-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

A mixture of Example 194f (150 mg, 0.294 mmol) and ethylamine (25% inethanol wt/wt) (5 mL, 0.832 mmol) was sealed and heated at 78° C. for 2day. The reaction mixture was cooled to ambient temperature andconcentrated. The residue was purified by reverse phase preparative HPLC(C18, 30-60% acetonitrile in 0.01 N NH₄CO₃/water) to give the titlecompound (25 mg, 0.049 mmol, 16.7% yield). ¹H NMR (400 MHz, DMSO-d₆) δ12.15 (brs, 1H), 8.30 (t, J=5.1 Hz, 1H), 7.94 (t, J=8.2 Hz, 1H),7.69-7.61 (m, 1H), 7.48-7.46 (m, 1H), 7.38 (d, J=7.9 Hz, 1H), 6.88-6.77(m, 2H), 6.39-6.29 (m, 2H), 6.33-5.88 (m, 1H), 4.81-4.14 (m, 3H), 3.58(s, 3H), 3.34-3.32 (m, 2H), 3.01 (s, 3H), 1.24-1.15 (m, 3H). MS (ESI+)m/z 509.2 (M+H)⁺.

Example 1955-cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 195a2-cyclopropyl-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline

A 5 mL microwave vial was charged with Example 12b (0.2287 g, 0.608mmol), cyclopropylboronic acid (0.209 g, 2.432 mmol), cesium carbonate(0.990 g, 3.04 mmol) and dichloropalladium (II)bistriphenylphosphine(0.021 g, 0.030 mmol). The tube was sealed, and the mixture was spargedwith nitrogen for 30 minutes. Degassed dioxane (2.53 mL) and water(0.507 mL) were added. The reaction mixture was heated to 100° C.overnight. The reaction mixture was partitioned between ethyl acetateand water. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered andconcentrated. The reaction mixture was purified by flash chromatography(10-70% ethyl acetate/heptanes) to provide the title compound (0.143 g,70% yield).

Example 195b2-bromo-6-cyclopropyl-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline

A 250 mL round-bottomed flask was charged with Example 195a and aceticacid (1.41 mL) to give a tan solution. N-bromosuccinimide (0.079 g,0.445 mmol) was added. The reaction mixture was stirred at roomtemperature for 1.5 hours. The reaction was quenched with sodiumthiosulfate (10 mL 10%) and neutralized with saturated aqueous sodiumbicarbonate. The reaction mixture was extracted with ethyl acetate (2×).The combined organic layers were washed with saturated aqueous sodiumchloried and concentrated. The residue was purified by flashchromatography (silica gel, 10-70% ethyl acetate/heptanes) to providethe title compound (0.111 g, 63% yield).

Example 195c4-(3-cyclopropyl-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 250 mL round-bottomed flask was charged with Example 195b (0.111 g,0.268 mmol), Example if (0.104 g, 0.243 mmol), sodium carbonate (0.090g, 0.851 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.011 g,0.012 mmol), and1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.012 g,0.041 mmol). The solids were sparged with nitrogen for 30 minutes.Degassed dioxane (1.946 mL) and water (0.487 mL) were added. Thereaction mixture was heated at 60° C. for 3 hours. The reaction mixturewas cooled to room temperature and partitioned between ethyl acetate andwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 0-5% methanol/dichloromethane) to provide the title compound.(0.155 g, 100% yield).

Example 195d4-(3-cyclopropyl-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 100 mL round-bottomed flask was charged with Example 195c (0.1553 g,0.244 mmol), lithium hydroxide hydrate (0.102 g, 2.435 mmol), dioxane(1.826 mL) and water (0.609 mL). The reaction mixture was heated at 50°C. overnight. The reaction mixture was cooled to room temperature andpartitioned between ethyl acetate and water. The aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 0-5% methanol/dichloromethane) to providethe title compound. (0.0792 g, 67% yield).

Example 195e5-cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 250 mL round-bottomed flask was charge with Example 195d (0.0792 g,0.164 mmol), paraformaldehyde (0.074 g, 0.819 mmol) and tetrahydrofuran(1.638 mL). Titanium (IV) chloride (0.328 mL, 0.328 mmol) was added. Thereaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride, anddried over anhydrous magnesium sulfate and mercaptopropyl silica gel for1 hour. The slurry was filtered through a 10 g Celite SPE column andconcentrated. The residue was purified by flash chromatography (silicagel, 0-5% methanol/dichloromethane) to provide the title compound.(0.0609 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.79-11.84 (m, 1H),7.67 (d, J=2.0 Hz, 1H), 7.63 (s, 1H), 7.21 (d, J=2.5 Hz, 1H), 6.96-7.05(m, 1H), 6.95 (d, J=1.8 Hz, 1H), 6.59-6.68 (m, 1H), 6.24-6.34 (m, 1H),5.76 (s, 2H), 5.19 (d, J=16.3 Hz, 1H), 4.35-4.56 (m, 3H), 3.59 (s, 3H),2.95 (s, 3H), 2.07-2.18 (m, 1H), 0.83-0.94 (m, 1H), 0.62-0.72 (m, 2H),0.28-0.37 (m, 1H). MS (ESI+) m/z 496.1 (M+H)⁺.

Example 196 tert-butyl(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

A mixture of Example 5f (0.262 g, 0.763 mmol) and tert-butyl(4-oxocyclohexyl)carbamate (0.332 g, 1.526 mmol) in dichloromethane (17mL) was treated with acetic acid (0.437 mL, 7.630 mmol). The reactionmixture was stirred 60° C. for 1.5 hours, and then cooled to 0° C. andtreated with sodium triacetoxyborohydride (0.340 g, 1.526 mmol). Thereaction mixture was removed from 0° C. ice bath and stirred at ambienttemperature for 18 hours. The reaction mixture was quenched by slowaddition of saturated sodium bicarbonate solution and then extractedthree times with ethyl acetate. The combined organic layers were washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered and concentrated. The residue was purified by flashcolumn chromatography on silica gel, eluting with 1% methanol indichloromethane to afford the title compound as a mixture of cis andtrans isomers (0.304 g, 0.543 mmol, 74% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 11.87-11.77 (m, 2H), 7.73-7.66 (m, 2H), 7.59-7.52 (m, 2H),7.31-7.12 (m, 6H), 6.81-6.70 (m, 1H), 6.53-6.48 (m, 1H), 4.54-4.30 (m,6H), 4.10-3.90 (m, 2H), 3.67-3.57 (m, 6H), 3.30-3.23 (m, 1H), 3.16-3.06(m, 1H), 2.94 (s, 6H), 2.78-2.68 (m, 1H), 2.62-2.55 (m, 1H), 1.96-1.47(m, 8H), 1.39-1.32 (m, 18H), 1.26-1.13 (m, 6H), 0.95-0.85 (m, 2H)). MS(ESI+) m/z 541.2 (M+H)⁺.

Example 197 tert-butyl((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

Example 196 (0.025 mg, 0.046 mmol), a mixture of cis and trans isomers,was purified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 5-70%gradient). Fractions of the first eluted isomer were collected,concentrated, and held under vacuum to remove residual trifluoroaceticacid to give the title compound (0.008 g, 0.015 mmol). ¹H NMR (500 MHz,DMSO-d₆) δ 11.81 (s, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.24-7.21 (m, 1H),7.18-7.12 (m, 2H), 6.51 (d, J=8.0 Hz, 1H), 4.45 (bs, 4H), 3.62 (s, 3H),3.15-3.06 (m, 1H), 2.94 (s, 3H), 2.58 (t, J=10.9 Hz, 1H), 1.81-1.55 (m,4H), 1.33 (s, 9H), 1.20-1.16 (m, 2H), 0.94-0.87 (m, 2H). MS (ESI+) m/z541.0 (M+H)⁺.

Example 1984-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 198a 4-chloro-N-(4-((methylsulfonyl)methyl)phenyl)aniline

A 20 mL microwave vial was charged with 4-chloroaniline (0.129 g, 1.012mmol), Example 9a (0.2522 g, 1.012 mmol), diacetoxypalladium (9.09 mg,0.040 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.039g, 0.081 mmol), cesium carbonate (0.462 g, 1.417 mmol), toluene (8.44mL) and tert-butanol (1.687 mL). The tube was sealed, and the reactionmixture was heated in a Biotage Creator microwave at 150° C. for 15minutes fixed hold time. The reaction mixture was filtered through aCelite SPE column (2 g) and rinsed with ethyl acetate. The reactionmixture was washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by flash chromatography (silica gel, 20-100% ethylacetate/heptanes) to provide the title compound. (0.255 g, 85% yield).

Example 198b2-bromo-N-(4-chlorophenyl)-4-((methylsulfonyl)methyl)aniline

A 250 mL round-bottomed flask was charged with Example 198a (0.2553 g,0.863 mmol) and acetic acid (8.63 mL). N-bromosuccinimide (0.154 g,0.863 mmol) was added in 2 portions 10 minutes apart. The reactionmixture was stirred at room temperature for 4 hours. The reactionmixture was quenched with sodium thiosulfate (30 mL, 10%) and dilutedwith water. The reaction mixture was extracted with ethyl acetate (2×).The combined organic layers were washed with 2N sodium hydroxide untilthe pH of the aqueous was >7, followed by washing with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 50-100% ethyl acetate/heptanes) to provide the title compound.(0.198 g, 61% yield).

Example 198c4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 250 mL round-bottomed flask was charged with Example 198b (0.1981 g,0.529 mmol), Example if (0.206 g, 0.481 mmol), sodium carbonate (0.178g, 1.682 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.022 g,0.024 mmol), and1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.024 g,0.082 mmol). The solids were flow purged with nitrogen for 1 hour.Degassed dioxane (4.0 mL) and water (1.0 mL) were added. The reactionmixture was heated at 60° C. for 3 hours. The reaction mixture wascooled to room temperature and partitioned between ethyl acetate andwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (0-5%methanol/dichloromethane) to provide a tan solid. The solid wastriturated with dichloromethane and heptanes and filtered to provide thetitle compound. (0.167 g, 58% yield).

Example 198d4-(2-((4-chlorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A 4 mL vial was charged with Example 198c (0.1673 g, 0.281 mmol),lithium hydroxide hydrate (0.118 g, 2.81 mmol), dioxane (1.40 mL) andwater (0.47 mL). The reaction mixture was heated at 50° C. overnight.The reaction mixture was cooled to room temperature and partitionedbetween water and ethyl acetate. The organic layer was washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 0-5% methanol/dichloromethane) to providethe title compound. (0.0795 g, 64% yield).

Example 198e4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A 250 mL round-bottomed flask was charged with Example 198d (0.0794 g,0.180 mmol). paraformaldehyde (0.081 g, 0.898 mmol), and tetrahydrofuran(1.797 mL). Titanium (IV) chloride (0.359 mL, 0.359 mmol) was added. Thereaction mixture was stirred at room temperature for 1 hour. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by flash chromatography (silica gel, 0-5%methanol/dichloromethane) to provide the title compound (0.0596 g, 73%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (bs, 1H), 7.92 (d, J=2.0 Hz,1H), 7.61 (s, 1H), 7.45 (dd, J=7.9, 1.9 Hz, 1H), 7.34 (d, J=5.5 Hz, 2H),6.98 (d, J=9.1 Hz, 2H), 6.42 (d, J=9.0 Hz, 2H), 5.13 (s, 1H), 4.37-4.66(m, 3H), 3.56 (s, 3H), 3.00 (s, 3H). MS (ESI+) m/z 454.1 (M+H)⁺.

Example 1994-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile

To the suspension of Example 58m (50 mg, 0.101 mmol) and triethylamine(0.028 mL, 0.201 mmol) in tetrahydrofuran (1 mL) at 0° C. was addedtrifluroracetic anhydride (0.043 mL, 0.302 mmol) dropwise and thereaction mixture was stirred at ambient temperature for further 60minutes.The solvent was removed and the residue was purified by reversephase HPLC (C8 column, CH₃CN/water (0.01 N ammonium carbonate, 25%-55%)to give the title compound (5 mg, 10.44 μmol, 10% yield) as grey solid.¹H NMR (400 MHz, DMSO-d₆) δ 13.36 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H),7.50 (d, J=9.5 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H), 7.06 (d, J=9.0 Hz, 2H),6.35 (d, J=9.0 Hz, 2H), 5.23-5.13 (m, 1H), 4.70-4.47 (m, 3H), 3.58 (s,3H), 3.01 (s, 3H). MS (ESI+) m/z 479.0 (M+H)⁺.

Example 2004-(2,4-difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 200a ethyl4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate

Example 12d (89 mg, 0.20 mmol) and ethyl 2-oxoacetate (0.119 mL, 0.600mmol) were combined in tetrahydrofuran (2 mL). To this suspension wasadded 1M titanium(IV) chloride in dichloromethane (0.400 mL, 0.400mmol). The reaction mixture was stirred at ambient temperature for 20hours, and partitioned with ethyl acetate and water. The organic layerwas washed with saturated aqueous sodium chloride, dried with anhydroussodium sulfate, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 2-4% methanol in dichloromethane) toprovide the title compound (78 mg, 74%).

Example 200b4-(2,4-difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To a solution of Example 200a (76.0 mg, 0.144 mmol) in tetrahydrofuran(2 mL) was added 1.0 M lithium aluminum hydride in tetrahydrofuran(0.144 mL, 0.144 mmol) dropwise at 0° C. The reaction mixture wasstirred at ambient temperature for 2 hours, and partitioned with ethylacetate and water. The organic layer was washed with saturated aqueoussodium chloride, dried with anhydrous sodium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 2-5% methanol in dichloromethane) to provide the title compound (45mg, 64%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (d, J=2.1 Hz, 1H), 7.78 (d,J=1.8 Hz, 1H), 7.66 (s, 1H), 7.60-7.49 (m, 1H), 7.21-7.14 (m, 2H),7.06-6.96 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 5.18 (dd, J=9.2, 5.4 Hz, 1H),4.99 (t, J=4.6 Hz, 1H), 4.52-4.39 (m, 2H), 3.64 (s, 3H), 3.48-3.34 (m,2H), 2.93 (s, 3H). MS (ESI+) m/z 486 (M+H)⁺.

Example 2014-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrileExample 201a4-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylicacid

Example 201a was prepared according to the procedure used for thepreparation of Example 581, substituting Example 127d for Example 58k,to provide the title compound.

Example 201b4-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 201b was prepared according to the procedure used for thepreparation of Example 58m, substituting Example 201a for Example 581,to provide the title compound.

Example 201c4-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile

Example 201c was prepared according to the procedure used for thepreparation of Example 199, substituting Example 201b for Example 58m,to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 7.92 (d,J=7.8 Hz, 1H), 7.84 (s, 1H), 7.52-7.47 (m, 2H), 7.36 (d, J=7.6 Hz, 1H),7.05 (d, J=9.1 Hz, 2H), 6.33 (d, J=9.1 Hz, 2H), 5.20-5.15 (m, 1H),4.66-4.63 (m, 1H), 3.57 (s, 3H). MS (ESI+) m/z 387.1 (M+H)⁺.

Example 2024-(2,4-difluorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

A mixture of Example 208i (250 mg, 0.289 mmol) and ethylamine (25% inethanol wt/wt) (5 mL, 1.386 mmol) was sealed and heated at 78° C. for 2days. The mixture was cooled to ambient temperature and the resultingsolid was collected by filtration and washed with methanol severaltimes. The solid was then purified by reverse phase preparative HPLC(C18, 30-60% acetonitrile/0.01 N NH₄CO₃ in water) to give the titlecompound (30 mg, 0.057 mmol, 19.71% yield) as white solid. ¹H NMR (400MHz, DMSO-d₆) δ 12.15 (s, 1H), 8.26 (d, J=4.8 Hz, 1H), 7.82 (d, J=1.7Hz, 1H), 7.71 (s, 1H), 7.29-7.22 (m, 1H), 7.21-7.07 (m, 1H), 7.02-6.89(m, 3H), 5.15 (brs, 1H), 4.49 (s, 2H), 3.66 (s, 3H), 3.29-3.26 (m, 3H),2.96 (s, 3H), 1.14 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 527.2 (M+H)⁺.

Example 2034-(4-cyanophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

A mixture of Example 59 (100 mg, 0.190 mmol), potassiumhexacyanoferrate(II) trihydrate (17.70 mg, 0.042 mmol), Pd2(dba)₃ (8.72mg, 9.52 μmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(X-Phos) (9.08 mg, 0.019 mmol), palladium(II) acetate (4.28 mg, 0.019mmol) and Cs₂CO₃ (93 mg, 0.286 mmol) in dioxane (6 mL) and water (1.5mL) was sealed and heated at 130° C. under microwave for 3 hours. Thereaction mixture was filtered through Celite and washed with ethylacetate and then concentrated. The residue was purified by reverse phaseHPLC (C18, CH₃CN/water (0.01N ammonium carbonate), 25-55% gradient) togive the title compound (8.4 mg, 0.016 mmol, 8.55% yield) as pale solid.¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (s, 1H), 8.35 (t, J=5.0 Hz, 1H), 7.96(d, J=1.7 Hz, 1H), 7.71 (s, 1H), 7.52-7.49 (m, 1H), 7.45-7.37 (m, 3H),6.47 (d, J=7.6 Hz, 2H), 5.98 (d, J=17.0 Hz, 1H), 4.67-4.63 (m, 1H), 4.54(d, J=2.3 Hz, 1H), 4.51-4.50 (m, 1H), 3.59 (s, 3H), 3.42-3.36 (m, 2H),3.02 (s, 3H), 1.20 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 516.2 (M+H)⁺.

Example 204(S)-2-((4-(2,4-difluorophenyl)-10-mmethylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione

Preparatory chiral SFC separation of the product from Example 117 (0.019g) on an (S,S) WHELK-O 1 column (21 mm×250 mm, 5 micron) eluting with a4:6 mixture of 0.1% diethylamine in methanol/carbon dioxide afforded thetitle compound. The stereochemistry was randomly assigned to this firsteluted peak (5.004 minutes, 98% ee, 5.1 mg, 64% recovery). %). ¹H NMR(500 MHz, DMSO-d₆) δ 11.78 (d, J=1.83 Hz, 1H), 7.93 (d, J=1.53 Hz, 1H),7.81-7.86 (m, 4H), 7.76 (s, 1H), 7.24-7.30 (m, 1H), 7.21 (dd, J=8.24,1.83 Hz, 1H), 7.09-7.15 (m, 1H) 6.99-7.05 (m, 1H), 6.96 (d, J=2.44 Hz,1H), 6.92 (d, J=8.24 Hz, 1H), 5.44 (dd, J=9.92, 5.34 Hz, 1H), 4.51-4.56(m, 1H), 4.44-4.48 (m, 1H), 3.87 (dd, J=13.28, 5.34 Hz, 1H), 3.66 (s,3H), 3.52 (dd, J=13.28, 10.22 Hz, 1H), 2.98 (s, 3H). MS (ESI+) m/z 615(M+H)⁺.

Example 205(R)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione

Preparatory chiral SFC separation of the product from Example 117 (0.019g) on an (S,S) WHELK-O 1 column (21 mm×250 mm, 5 micron) eluting with a4:6 mixture of 0.1% diethylamine in methanol/carbon dioxide afforded thetitle compound. The stereochemistry was randomly assigned to this secondeluted peak (5.732 minutes, >99% ee, 5.6 mg, 70% recovery). ¹HNMR (500MHz, DMSO-d₆) δ 11.78 (d, J=1.83 Hz, 1H), 7.93 (d, J=1.53 Hz, 1H),7.81-7.86 (m, 4H), 7.76 (s, 1H), 7.24-7.30 (m, 1H), 7.21 (dd, J=8.24,1.83 Hz, 1H), 7.09-7.15 (m, 1H) 6.99-7.05 (m, 1H), 6.96 (d, J=2.44 Hz,1H), 6.92 (d, J=8.24 Hz, 1H), 5.44 (dd, J=9.92, 5.34 Hz, 1H), 4.51-4.56(m, 1H), 4.44-4.48 (m, 1H), 3.87 (dd, J=13.28, 5.34 Hz, 1H), 3.66 (s,3H), 3.52 (dd, J=13.28, 10.22 Hz, 1H), 2.98 (s, 3H). MS (ESI+) m/z 615(M+H)⁺.

Example 2064-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrileExample 206a2,6-dibromo-N-(2,4-difluorophenyl)-4-((methylsulfonyl)methyl)aniline

A 500 mL round-bottomed flask was charged with Example 12a (3.000 g,7.97 mmol) and trifluoroacetic acid (80 mL) to give a colorlesssolution. The reaction mixture was cooled to 0° C. N-bromosuccinimide(1.419 g, 7.97 mmol) was added in two portions 10 minutes apart. Thecold bath was removed, and the reaction mixture was stirred at ambienttemperature for 2 hours. The solvent was removed, and 200 mL 2N sodiumhydroxide, 50 mL 10% sodium thiosulfate, and 200 mL ethyl acetate wereadded. The reaction mixture was stirred for 30 minutes. The layers wereseparated, and the organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated onto silica gel. The reaction mixture was purified by flashchromatography (20-100% ethyl acetate:heptanes) to provide a white solid(2.48 g, 68%).

Example 206b4-(3-bromo-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 206b was prepared according to the procedure used for thepreparation of Example 6b, substituting Example 206a for Example 6a, toprovide the title compound as a yellow solid (0.0872 g, 50% yield).

Example 206c4-(3-bromo-2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 206c was prepared according to the procedure used for thepreparation of Example 12d, substituting Example 206b for Example 12c,to provide the title compound as a red oil (0.0552 g, 44% yield).

Example 206d5-bromo-4-(2,4-difluorophenyl)-10-mmethylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 206d was prepared according to the procedure used for thepreparation of Example 82, substituting Example 206c for Example 12d, toprovide the title compound as a yellow solid (0.0352 g, 62% yield).

Example 206e4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrile

A 2 mL microwave tube was charged with zinc (II) cyanide (0.012 g, 0.099mmol) and dichlorobis(triphenylphosphine)palladium(II) (4.62 mg, 6.59tmol). Example 206d (0.0352 g, 0.066 mmol) and N,N-dimethylformamide(0.659 mL) were added. The tube was sealed, and the reaction mixture washeated in a Biotage Creator at 200° C. for 30 minutes fixed hold time.The reaction mixture was partitioned between ethyl acetate and water.The organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous magnesium sulfate and mercaptopropyl silica gel,filtered and concentrated. The reaction mixture was purified by flashchromatography (0-5% methanol:dichloromethane) to provide a white solid(0.0209 g, 66% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.95 (bs, 1H), 8.24(d, J=2.0 Hz, 1H), 7.81 (s, 1H), 7.78 (d, J=1.9 Hz, 1H), 7.24 (s, 1H),6.99-7.20 (m, 1H), 6.73 (td, J=8.5, 2.8 Hz, 1H), 6.45 (td, J=9.5, 5.8Hz, 1H), 5.05-5.14 (m, 1H), 4.43-4.80 (m, 3H), 3.62 (s, 3H), 3.02 (s,3H). MS (ESI+) m/z 481.0 (M+H)⁺.

Example 20710-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 207a4-(2-amino-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 1f (2.0 g, 4.67 mmol), Example 5c (1.6 g, 5.14 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.128 g, 0.14 mmol),1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.136 g,0.467 mmol) and sodium carbonate (2.13 g, 20.1 mmol) were combined andsparged with nitrogen for 30 minutes. To this mixture were addednitrogen-sparged 1,4-dioxane (24 mL) and water (6 mL) via syringe. Thereaction mixture was stirred at 60° C. for 5 hours, cooled to ambienttemperature and partitioned between ethyl acetate and water. The organiclayer was washed with saturated aqueous sodium chloride, treated with3-mercaptopropyl-functionalized silica gel for 20 minutes, dried overanhydrous magnesium sulfate, filtered through a plug of Celite, andconcentrated. The residue was purified by flash chromatography (silicagel, 0-100% ethyl acetate in dichloromethane). The product was furtherpurified by trituration with diethyl ether and then dried in a vacuumoven at 70° C. to give 2.06 g (91%) of the title compound.

Example 207b6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 207a (0.4 g, 0.824 mmol), 2-bromopyridine (0.325 g, 2.06 mmol),diacetoxypalladium (0.046 g, 0.206 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.196g, 0.412 mmol) and cesium carbonate (0.537 g, 1.65 mmol) were combinedin a 20-mL microwave vial equipped with a magnetic stirbar. Toluene (6.6mL) and tert-butanol (1.65 mL) were added and the mixture was reacted ina Biotage microwave reactor at 160° C. for 1 hour. The reaction sequencewas repeated and then the two reaction mixtures were combined andfiltered through a fritted funnel to remove the Pd solids. The filtratewas partitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, treated with3-mercaptopropyl-functionalized silica gel for 20 minutes, dried overanhydrous magnesium sulfate, filtered through a plug of Celite, andconcentrated. The residue was purified by flash chromatography (silicagel, 0-50% ethyl acetate in dichloromethane and then 5-7% methanol indichloromethane) to give 0.211 g (23%) of the title compound.

Example 207c6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 207b (0.21 g, 0.373 mmol) in 1,4-dioxane (5 mL) andwater (1.7 mL) was treated with lithium hydroxide.H₂O (0.157 g, 3.73mmol) and N,N,N-trimethylhexadecan-1-aminium bromide (0.0041 g, 0.011mmol) and heated at 63° C. for 3.5 hours, stirred at ambient temperatureovernight and then heated at 75° C. for another 1.5 hours. The reactionmixture was cooled to ambient temperature and neutralized withhydrochloric acid solution (2 N aqueous). The resulting mixture was thenpartitioned between ethyl acetate and water, washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered and concentrated. The residue was purified by flashchromatography (silica gel, 0-25% methanol in dichloromethane) to give0.15 g (99%) of the title compound.

Example 207d10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stirbar was addedExample 207c (0.15 g, 0.367 mmol), paraformaldehyde (0.033 g, 1.1 mmol),and acetic acid (7.3 mL). The vial was capped and heated at 75° C. for55 minutes. A second reaction mixture was run as follows. To a 5-mLmicrowave vial equipped with a magnetic stirbar was added Example 207c(0.082 g, 0.2 mmol), paraformaldehyde (0.018 g, 0.6 mmol), and aceticacid (4 mL). The vial was capped and heated at 75° C. for 45 minutes.The reaction mixtures were combined and concentrated. To the residue wasadded 1,4-dioxane (5.7 mL) and sodium hydroxide solution (4 N aqueous)(1.4 mL, 5.67 mmol). The reaction mixture heated at 60° C. for 1 hour,cooled to ambient temperature and neutralized with hydrochloric acidsolution (2 N aqueous). The resulting mixture was then partitionedbetween ethyl acetate and water and washed with saturated aqueous sodiumchloride. The combined aqueous layers were extracted with ethyl acetateuntil no product was detected. The organic layers were combined, driedover anhydrous magnesium sulfate, filtered and concentrated. The residuewas purified by reverse phase HPLC (C18, acetonitrile/water (0.1% TFA),10-60%) to provide 0.271 g (89%) of the title compound as the TFA salt.¹H NMR (500 MHz, DMSO-d₆) δ 11.84 (d, J=1.53 Hz, 1H), 7.98 (dd, J=4.88,1.22 Hz, 1H), 7.91 (d, J=1.83 Hz, 1H), 7.63 (s, 1H), 7.43 (m, 1H), 7.36(d, J=7.93 Hz, 1H), 7.29 (m, 2H), 6.51 (ddd, J=7.02, 4.88, 0.61 Hz, 1H),6.16 (d, J=8.24 Hz, 1H), 5.79 (d, J=15.56 Hz, 1H), 4.62 (d, 1H), 4.52(d, 1H), 4.24 (d, J=15.56 Hz, 1H), 3.57 (s, 3H), 3.01 (s, 3H). MS (ESI+)m/z 421.1 (M+H)⁺.

Example 208 ethyl4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylateExample 208a 4-bromo-7-methoxy-1H-pyrrolo[2,3-c]pyridine

To a solution of 5-bromo-2-methoxy-3-nitropyridine (50 g, 215 mmol) intetrahydrofuran (2000 mL) was added vinyl-magnesium bromide (800 mL, 644mmol) dropwise at −70° C., and the mixture was stirred between −70° C.and −60° C. for 2 hours. The reaction mixture was quenched with 20%aqueous NH₄Cl, extracted with ethyl acetate, dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure to get a brownresidue. This material was purified by column chromatography on silicagel (eluted with petroleum ether:ethyl acetate=10:1) to give a crudeproduct, which was triturated with dichloromethane and dried undervacuum to give the title compound (20 g, 41.1% yield) as a light yellowsolid.

Example 208b 4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine

To a solution of Example 208a (44 g, 194 mmol) in tetrahydrofuran (600mL) was added sodium hydride (6.98 g, 290 mmol) portion-wise at 0° C.The mixture was stirred for 1 hour. Then 4-methylbenzene-1-sulfonylchloride (55.4 g, 290 mmol) was added to the mixture portion-wise at 0°C. After stirring at ambient temperature for 2 hours, the reactionmixture was quenched with 20% aqueous ammonium chloride. The mixture wasextracted with ethyl acetate three times and partitioned. The combinedorganic layers were dried (anhydrouse sodium sulfate), and filtered. Thefiltrate was concentrated in vacuum to afford a residue which wasrecrystallized from ethyl acetate and petroleum ether to give the titlecompound (52 g, 70.4% yield) as light yellow solid.

Example 208c ethyl4-bromo-7-methoxy-1-tosyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

To a solution of Example 208b (10.5 g, 27.5 mmol) in tetrahydrofuran(170 mL) was added dropwise lithium diisopropylamide (20.7 mL, 41.40mmol) at −70° C. and the reaction mixture was stirred between −70° C.and −50° C. for 45 minutes. To the stirred resulting mixture at −70° C.was added ethyl carbonochloridate (4.48 g, 41.3 mmol) dropwise. Thereaction mixture was stirred at −70° C. for 1.5 hours, quenched with 20%aqueous ammonium chloride, and extracted with ethyl acetate (150 mL).The combined organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated in vacuum to give the crude product, whichwas washed with dichloromethane to give the title compound (10 g, 80%)as a white solid.

Example 208d ethyl4-bromo-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

To a mixture of Example 208c (32.5 g, 71.7 mmol) and sodium iodide(16.12 g, 108 mmol) in acetonitrile (554 mL) was addedchlorotrimethylsilane (11.68 g, 108 mmol) dropwise at ambienttemperature. The resulting mixture was stirred at ambient temperaturefor 1 hour. Water (0.685 g, 38.0 mmol) was added dropwise to thereaction mixture and the mixture was stirred at 65° C. for 3 hours. Thereaction mixture was cooled to ambient temperature and filtered. Theprecipitate was dissolved in dichloromethane. The mixture was filteredagain and the combined filtrate was concentrated under reduced pressureto give a brown solid which was washed with petroleum anddichloromethane to afford the title compound (23 g, 52.4 mmol, 73.0%yield) as a light yellow solid.

Example 208e ethyl4-bromo-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

To a solution of Example 208d (7.5 g, 17.07 mmol) in tetrahydrofuran(100 mL) was added sodium hydride (0.520 g, 21.68 mmol) in portions at0° C., and the reaction mixture was stirred for 30 minutes. Iiodomethane(3.64 g, 25.6 mmol) was added dropwise to the above mixture at 0° C. Theresulting mixture was stirred at ambient temperature for 3 hours andanother portion of iodomethane (3.64 g, 25.6 mmol) was added at 0° C.The reaction mixture was stirred at ambient temperature for 12 hours,quenched with 20% aqueous ammonium chloride and extracted with ethylacetate three times. The combined mixtures were dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The resulting residue waspurified by column chromatography on silica gel, eluting with 1:1 ethylacetate/hexanes to provide a yellow crude product which was washed withmethanol to give the title compound (15.3 g, 80% yield).

Example 208f ethyl6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 208f was prepared according to the procedure used for thepreparation of Example if, substituting Example 208e for Example 1e, toprovide the title compound.

Example 208g ethyl4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

Example 208g was prepared according to the procedure used for thepreparation of Example 5d, substituting Example 12b for Example 5c, andExample 208f for Example if, respectively, to provide the titlecompound.

Example 208h ethyl4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylate

A mixture of ethyl Example 208g (0.2 g, 0.299 mmol) in dioxane (2 mL)and ethanol (0.5 mL) was treated with sodium hydroxide (0.747 mL, 1.493mmol) at ambient temperature. The reaction mixture was heated to 60° C.over 2 minutes. After cooling to ambient temperature, the reactionmixture was partitioned between 1.0 N HCl and ethyl acetate. The organiclayer was separated, and the aqueous layer was extracted with additionalethyl acetate twice. The combined organic layers were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated to give the title compound (0.15 g,0.291 mmol, 97% yield).

Example 208i ethyl4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate

Example 208i was prepared according to the procedure used for thepreparation of Example 58k, substituting Example 208h for Example 58j,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 12.67 (s,1H), 7.84 (d, J=2.14 Hz, 1H), 7.72 (s, 1H), 7.29 (dd, J=8.24, 1.83 Hz,1H), 7.09-7.13 (m, 1H), 7.03 (d, J=7.93 Hz, 1H), 6.84-6.89 (m, 1H),6.75-6.81 (m, 1H), 5.09 (s, 2H), 4.49 (s, 2H), 4.29 (q, J=7.02 Hz, 1H),3.64 (s, 3H), 2.96 (s, 3H), 1.34 (t, J=7.02 Hz, 3H). MS (ESI+) m/z 528.1(M+H)⁺.

Example 2094-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamideExample 209a4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylicacid

Example 209a was prepared according to the procedure used for thepreparation of Example 581, substituting Example 208i for Example 58k,to provide the title compound.

Example 209b4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

Example 209b was prepared according to the procedure used for thepreparation of Example 58m, substituting Example 209a for Example 581,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 12.19 (s,1H), 7.82 (d, J=2.14 Hz, 1H), 7.72 (s, 2H), 7.70 (s, 1H), 7.53 (s, 1H),7.26 (dd, J=8.09, 1.98 Hz, 1H), 7.05-7.11 (m, 1H), 6.98 (d, J=7.93 Hz,1H), 6.90-6.93 (m, 2H), 6.75-6.81 (m, 1H), 5.14 (s, 2H), 4.48 (s, 2H),3.66 (s, 3H), 2.95 (s, 3H). MS (ESI+) m/z 499.1 (M+H)⁺.

Example 2104-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile

Example 210 was prepared according to the procedure used for thepreparation of Example 199, substituting Example 209b for Example 58m,to provide the title compound. ¹H NMR (500 MHz, DMSO-d₆) δ 13.32 (s,1H), 7.89 (d, J=1.83 Hz, 1H), 7.82 (s, 1H), 7.32 (dd, J=8.24, 1.83 Hz,1H), 7.12-7.15 (m, 1H), 7.08 (d, J=8.24 Hz, 1H), 6.83-6.88 (m, 1H),6.71-6.77 (m, 1H), 4.86 (s, 2H), 4.51 (s, 2H), 3.65 (s, 3H), 2.97 (s,3H). MS (ESI+) m/z 481.1 (M+H)⁺.

Example 21110-methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 211a6-methyl-4-(5-((methylsulfonyl)methyl)-2-((3,4,5-trimethoxyphenyl)amino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 5d (0.075 g, 0.154 mmol),5-bromo-1,2,3-trimethoxybenzene (0.114 g, 0.463 mmol), cesium carbonate(0.101 g, 0.309 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(XPhos)(0.0368 g, 0.077 mmol), and palladium (II) acetate (0.0087 g,0.039 mmol) in toluene (3 mL) and tert-butanol (0.75 mL) under argon washeated in a sealed tube in a microwave reactor at 160° C. for 2 hours.The reaction mixture was cooled to ambient temperature and filteredthrough filter paper. The resulting filtrate was concentrated to neardryness and mixed with ethanol (2 mL), tetrahydrofuran (4 mL), andexcess 5N sodium hydroxide solution (2 mL). The reaction mixture wasstirred at ambient temperature for 1 hour then concentrated to 5 mL andpartitioned between ammonium chloride aqueous solution and ethylacetate. The aqueous phase was extracted twice more with ethyl acetate.The combined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by flash column chromatography onsilica gel eluting with 3% methanol in dichloromethane to afford thetitle compound (0.020 g, 0.040 mmol, 26% yield).

Example 211b10-methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 211a (0.020 g, 0.040 mmol) and paraformaldehyde(0.006 g, 0.201 mmol) in tetrahydrofuran (2 mL) at ambient temperatureunder argon was treated with a 1M solution of titanium tetrachloride(0.080 mL, 0.080 mmol). The reaction mixture suspension was stirred atambient temperature for 1 hour and then partitioned between ethylacetate and saturated sodium bicarbonate. The aqueous layer wasextracted three times with ethyl acetate. The combined organic layerswere washed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was trituratedwith methanol to give the title compound (0.0026 g, 13% yield). ¹H NMR(500 MHz, DMSO-d₆) δ 11.83 (s, 1H), 7.92 (s, 1H), 7.64 (s, 1H),7.46-7.29 (m, 3H), 5.71 (s, 2H), 5.49-4.66 (m, 2H), 4.56 (s, 2H), 3.57(s, 3H), 3.51 (s, 6H), 3.45 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 510.3(M+H)⁺.

Example 2124-(4-aminocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 196 (0.240 g, 0.444 mmol) in dichloromethane (10mL) was treated excess with trifluoroacetic acid (1 mL) and stirred atambient temperature for 6 hours. The reaction mixture was concentratedand dried under vacuum to afford a solid residue which was partitionedbetween saturated sodium carbonate solution and ethyl acetate. Theaqueous phase was extracted twice more with ethyl acetate and twice withdichloromethane. The combined organic extracts were dried with magnesiumsulfate and concentrated. The residue was triturated with ethyl acetateand filtered to give the title compound (0.0066 g, 0.015 mmol, 45%yield). ¹H NMR (501 MHz, DMSO-d₆) δ 11.80 (bs, 1H), 7.68 (s, 1H),7.51-7.45 (m, 1H), 7.27-7.09 (m, 3H), 4.44-4.39 (m, 2H), 4.18 (s, 2H),3.10 (bs, 2H), 3.61 (s, 3H), 2.90 (s, 3H), 2.82-2.42 (m, 2H), 1.68-1.45(m, 4H), 1.36-1.17 (m, 3H), 0.88-0.81 (m, 1H). MS (ESI+) m/z 440.8(M+H)⁺.

Example 2134-(3,5-difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 213a4-(2-((3,5-difluoropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 207a, 2-bromo-3,5-difluoropyridine (0.245 g, 1.263 mmol),diacetoxypalladium (0.032 g, 0.143 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.137g, 0.287 mmol) and cesium carbonate (0.374 g, 1.148 mmol) were combinedin a 20-mL microwave vial equipped with a magnetic stirbar. Toluene (4.4mL) and tert-butanol (1.1 mL) were added and the reaction mixture wasreacted in a Biotage microwave reactor at 160° C. for 1 hour. Thereaction mixture was cooled to ambient temperature, diluted with ethylacetate and water and filtered through a plastic fritted funnel toremove the Pd solids. The filtrate was poured into a separatory funneland the layers were separated. The organic layer was washed with waterand saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered and concentrated. The residue was purified by flashchromatography (silica gel, 0-70% ethyl acetate in dichloromethane) togive 0.229 g (71%) of the title compound.

Example 213b4-(2-((3,5-difluoropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To Example 213a (0.2129 g, 0.356 mmol) in tetrahydrofuran (8 mL) wasadded tetrabutylammonium fluoride (0.28 g, 1.07 mmol). The reactionmixture was heated at 60° C. for 45 minutes, cooled to ambienttemperature, partitioned between ethyl acetate and water, washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 0-8% methanol in dichloromethane) to givethe title compound as a mixture. It was further purified by flashchromatography (silica gel, 40-75% ethyl acetate in dichloromethane with2-4% methanol as an additive) to give 0.116 g (73%) of the titlecompound.

Example 213c4-(3,5-difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stirbar was addedExample 213b (0.116 g, 0.261 mmol), paraformaldehyde (0.024 g, 0.783mmol), and acetic acid (4.5 mL). The vial was capped and heated at 75°C. for 50 minutes. The reaction mixture was cooled to ambienttemperature, concentrated under vacuum, diluted with 1,4-dioxane (6 mL),treated with sodium hydroxide solution (4 M aqueous, 1.3 mL, 5.22 mmol)and heated at 75° C. for 1 hour. The reaction mixture was cooled toambient temperature, concentrated under vacuum, slurried in water andneutralized with hydrochloric acid solution (2 N aqueous). The solid wascollected by filtration and rinsed with additional water (20 mL). Thesolid was purified by reverse phase HPLC (C18, acetonitrile/water (0.1%TFA), 10-70%) to provide 0.09 g (61%) of the title compound as the TFAsalt. ¹H NMR (500 MHz, DMSO-d₆) δ 11.87 (s, 1H), 8.06 (d, J=1.83 Hz,1H), 7.83 (s, 1H), 7.67 (s, 1H), 7.59 (m, 1H), 7.29 (d, J=7.93 Hz, 1H),7.25 (d, J=1.53 Hz, 1H), 7.13 (d, J=8.24 Hz, 1H), 5.95 (s, 1H), 4.52 (s,2H), 4.20 (s, 1H), 3.62 (s, 3H), 2.96 (s, 3H). MS (ESI+) m/z 457.1(M+H)⁺.

Example 2144-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 12d (66.5 mg, 0.150 mmol) and benzaldehyde (0.076 mL, 0.75 mmol)were combined in tetrahydrofuran (2 mL). To this suspension was added 1Mtitanium(IV) chloride in toluene (0.300 mL, 0.300 mmol). The reactionmixture was stirred at ambient temperature for 72 hours, and partitionedwith ethyl acetate and water. The organic layer was washed withsaturated aqueous sodium chloride, dried with anhydrous sodium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 2-4% methanol in dichloromethane) to providethe title compound (65 mg, 82%). ¹H NMR (500 MHz, DMSO-d₆) δ 12.04 (d,J=2.0 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.28 (d, J=2.6 Hz,1H), 7.18-7.00 (m, 7H), 6.89-6.79 (m, 3H), 6.47 (s, 1H), 4.39-4.29 (m,2H), 3.66 (s, 3H), 2.70 (s, 3H). MS (ESI+) m/z 532 (M+H)⁺.

Example 215(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

The product from Example 214 was purified by chiral chromatography on a(S,S) WHELK-O 1 column (21×250 mm, 5 micron), eluting with a 4:6 mixtureof 0.1% diethylamine in methanol/carbon dioxide. Fractions of the firsteluted enantiomer was collected and concentrated. The compound isolatedwas randomly assigned as (R) enantiomer. ¹H NMR (500 MHz, DMSO-d₆) δ12.04 (d, J=2.0 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.28 (d,J=2.6 Hz, 1H), 7.18-7.00 (m, 7H), 6.89-6.79 (m, 3H), 6.47 (s, 1H),4.39-4.29 (m, 2H), 3.66 (s, 3H), 2.70 (s, 3H). MS (ESI+) m/z 532 (M+H)⁺.

Example 216(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

The product from Example 214 was purified by chiral chromatography on a(S,S) WHELK-O Icolumn (21×250 mm, 5 micron), eluting with a 4:6 mixtureof 0.1% diethylamine in methanol/carbon dioxide. Fractions of the secondeluted enantiomer was collected and concentrated. The compound isolatedwas randomly assigned as (S) enantiomer. ¹H NMR (500 MHz, DMSO-d₆) δ12.04 (d, J=2.0 Hz, 1H), 7.71 (d, J=1.8 Hz, 1H), 7.68 (s, 1H), 7.28 (d,J=2.6 Hz, 1H), 7.18-7.00 (m, 7H), 6.89-6.79 (m, 3H), 6.47 (s, 1H),4.39-4.29 (m, 2H), 3.66 (s, 3H), 2.70 (s, 3H). MS (ESI+) m/z 532 (M+H)⁺.

Example 2174-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(naphthalen-1-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 12d (0.06 g, 0.135 mmol) and 1-naphthaldehyde (0.148 mL, 1.082mmol) were combined in tetrahydrofuran (1.353 mL) under nitrogen andtreated with 1M titanium(IV) chloride in toluene (1.082 mL, 1.082 mmol).The reaction mixture was heated at 70° C. for 24 hours, cooled toambient temperature, and partitioned between ethyl acetate and water.The organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, filtered, and concentrated.Purification by chromatography (silica gel, 1-5% methanol indichloromethane) afforded the title compound (0.015 g, 19%). ¹H NMR (400MHz, DMSO-d₆) δ 12.07 (s, 1H), 8.75 (d, J=8.85 Hz, 1H), 7.86 (d, J=7.93Hz, 1H), 7.69-7.75 (m, 3H), 7.61 (d, J=8.54 Hz, 1H), 7.55 (t, J=7.32 Hz,1H), 7.38 (d, J=1.53 Hz, 1H), 7.24 (d, J=2.44 Hz, 1H), 7.11-7.19 (m,1H), 6.98 (t, J=7.63 Hz, 1H), 6.65-6.73 (m, 2H), 6.60 (d, J=7.02 Hz,1H), 6.37-6.45 (m, 1H), 6.30 (d, J=7.93 Hz, 1H), 4.20-4.34 (m, 2H), 3.66(s, 3H), 2.59 (s, 3H). MS (ESI+) m/z 582 (M+H)⁺.

Example 2184-(2,4-difluorophenyl)-(3,3-²H₂)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 218 was prepared according to the procedure used for thepreparation of Example 82, substituting formaldehyde-d₂ for methyl4-oxobutanoate, to provide the title compound as a yellow solid (0.0352g, 62% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.85 (s, 1H), 7.86 (d, J=2.0Hz, 1H), 7.67 (s, 1H), 7.27 (dd, J=8.1, 2.0 Hz, 1H), 7.18 (d, J=2.5 Hz,1H), 7.08 (ddd, J=12.4, 9.0, 3.1 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H),6.80-6.88 (m, 1H), 6.76 (td, J=9.4, 5.9 Hz, 1H), 4.50 (bs, 2H), 3.63 (s,3H), 2.96 (s, 3H). MS (ESI+) m/z 458.1 (M+H)⁺.

Example 2194-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-neopentyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 12d (0.06 g, 0.135 mmol) and 3,3-dimethylbutyraldehyde (0.081 g,0.812 mmol) were combined in tetrahydrofuran (1.353 mL) under nitrogenand treated drop-wise with 1M titanium(IV) chloride in toluene (0.812mL, 0.812 mmol). The reaction mixture was stirred for 2 hours at 60° C.,cooled to ambient temperature, and partitioned between ethyl acetate andwater. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous sodium sulfate, filtered andconcentrated. Purification by chromatography (silica gel, 30-60% of 3:1ethyl acetate/ethanol in heptanes) afforded the title compound (0.010 g,14%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.81 (s, 1H), 7.91 (d, J=1.53 Hz,1H), 7.68 (s, 1H), 7.25 (dd, J=8.09, 1.68 Hz, 1H), 7.16 (d, J=2.44 Hz,1H), 7.06-7.13 (m, 1H), 6.98 (d, J=7.93 Hz, 1H), 6.73-6.80 (m, 1H),6.53-6.60 (m, 1H), 5.19 (dd, J=7.32, 4.88 Hz, 1H), 4.45-4.56 (m, 2H),3.63 (s, 3H), 2.94 (s, 3H), 1.67 (dd, J=13.73, 4.88 Hz, 1H), 1.20 (dd,J=13.73, 7.63 Hz, 1H), 0.89 (s, 9H). MS (ESI+) m/z 526 (M+H)⁺.

Example 2204-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((1-oxoisoindolin-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 220a 2-(2,2-dimethoxyethyl)isoindolin-1-one

A 5 mL microwave tube was charged with isoindolin-1-one (0.2544 g, 1.911mmol), cesium carbonate (1.245 g, 3.82 mmol) andN-methyl-2-pyrrolidinone (9.55 mL) to give a colorless solution.Bromoacetaldehyde dimethyl acetal (1.125 mL, 9.55 mmol) was added. Thetube was sealed, and the reaction mixture was heated in a BiotageCreator at 160° C. for 60 minutes fixed hold time. The reaction mixturewas partitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The reaction mixture waspurified by flash chromatography (20-70% ethyl acetate:heptane) toprovide a brown oil (0.179 g, 42% yield).

Example 220b4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((1-oxoisoindolin-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 220b was prepared according to the procedure used for thepreparation of Example 82, substituting Example 220a for methyl4-oxobutanoate, to provide the title compound as a white solid (0.0169g, 29% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.84 (m, 1H), 7.91 (d, J=2.0Hz, 1H), 7.75 (s, 1H), 7.51-7.66 (m, 3H), 7.47 (t, J=6.7 Hz, 1H),7.18-7.28 (m, 2H), 7.12 (ddd, J=11.9, 8.9, 3.0 Hz, 1H), 6.96 (ddd,J=17.9, 11.7, 5.4 Hz, 3H), 5.46 (dd, J=9.5, 5.8 Hz, 1H), 4.53 (d, J=15.7Hz, 2H), 4.46 (d, J=13.7 Hz, 1H), 4.17-4.26 (m, 1H), 3.89 (dd, J=13.4,5.7 Hz, 1H), 3.66 (s, 3H), 3.34-3.44 (m, 1H), 2.97 (s, 3H). MS (ESI−)m/z 599.2 (M−H)⁺.

Example 2214-(2,4-difluorophenyl)-3-(2,6-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 12d (53.2 mg, 0.120 mmol) and 2,6-dimethoxybenzaldehyde (100 mg,0.600 mmol) were combined in tetrahydrofuran (1 mL). To this suspensionwas added 1M titanium(IV) chloride in toluene (0.240 mL, 0.240 mmol).The reaction mixture was heated at 60° C. for 24 hours, cooled toambient temperature, and partitioned with ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride, driedwith anhydrous sodium sulfate, filtered, and concentrated. The residuewas purified by flash chromatography (silica gel, 2-4% methanol indichloromethane) to provide the title compound (8 mg, 11% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 11.62 (d, J=2.0 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H),7.69 (s, 1H), 7.16-6.73 (m, 7H), 6.60-6.34 (m, 3H), 4.52-4.30 (m, 2H),3.65 (s, 3H), 3.32 (s, 6H), 2.85 (s, 3H). MS (ESI+) m/z 592 (M+H)⁺.

Example 2224-(2,4-difluorophenyl)-3-(3,5-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 222 was prepared according to the procedure used for thepreparation of Example 221, substituting 3,5-dimethoxybenzaldehyde for2,6-dimethoxybenzaldehyde, to provide the title compound (39 mg, 55%).¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.69(s, 1H), 7.26 (d, J=1.7 Hz, 1H), 7.19-7.04 (m, 2H), 6.96-6.81 (m, 3H),6.34 (s, 1H), 6.27-6.18 (m, 3H), 4.46-4.31 (m, 2H), 3.66 (s, 3H), 3.56(s, 6H), 2.75 (s, 3H). MS (ESI+) m/z 592 (M+H)⁺.

Example 2233-(3,5-di-tert-butylphenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 223 was prepared according to the procedure used for thepreparation of Example 221, substituting 3,5-di-tert-butylbenzaldehydefor 2,6-dimethoxybenzaldehyde, to provide the title compound (60 mg,78%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.99 (d, J=1.8 Hz, 1H), 7.70-7.64 (m,2H), 7.29 (d, J=2.4 Hz, 1H), 7.18-7.09 (m, 1H), 7.07-6.99 (m, 2H), 6.96(s, 2H), 6.92-6.82 (m, 2H), 6.75 (d, J=8.1 Hz, 1H), 6.44 (s, 1H),4.41-4.22 (m, 2H), 3.66 (s, 3H), 2.64 (s, 3H), 1.08 (s, 18H). MS (ESI+)m/z 644 (M+H)⁺.

Example 224 methyl(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

A mixture of Example 212 (0.065 g, 0.148 mmol) andN,N-diisopropylethylamine (0.103 mL, 0.590 mmol) in dimethylformamide (5mL) under argon at ambient temperature was treated with dropwiseaddition of methyl chloroformate (0.012 mL, 0.148 mmol). The reactionmixture was stirred 2 hours at ambient temperature and then partitionedbetween aqueous ammonium chloride solution and ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered and concentrated to affordthe title compound (0.050 g, 0.100 mmol, 68% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 11.43 (s, 1H), 7.70-7.65 (m, 1H), 7.49-7.43 (m, 1H),7.28-7.14 (m, 2H), 7.09 (s, 1H), 6.60 (s, 0.5H), 6.37 (d, J=7.0 Hz,0.5H), 4.43-4.37 (m, 2H), 4.19 (s, 2H), 3.61 (s, 3H), 3.54-3.44 (m, 3H),3.42-3.10 (m, 1H), 2.89 (s, 3H), 2.85-2.66 (m, 1H), 1.74-1.45 (m, 4H),1.39-1.18 (m, 3H), 1.04-0.94 (m, 1H). MS (ESI+) m/z 499.1 (M+H)⁺.

Example 225 methyl((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

The geometric isomers of Example 224 were separated on reverse phaseHPLC (C18, CH₃CN/water (0.1% TFA), 5-40% gradient). Fractions of thefirst eluted isomer was collected and concentrated to provide the titlecompound (0.008 g, 0.016 mmol, 11% yield). ¹H NMR (400 MHz, DMSO-d₆) δ11.49 (s, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.49 (s, 1H), 7.28-7.18 (m, 2H),7.13 (d, J=2.5 Hz, 1H), 6.38 (s, 1H), 4.41 (s, 2H), 4.25 (s, 2H), 3.61(s, 3H), 3.47 (s, 3H), 3.21-3.11 (m, 1H), 2.89 (s, 3H), 2.79-2.71 (m,1H), 1.75-1.58 (m, 4H), 1.39-1.25 (m, 3H), 1.02-0.94 (m, 1H). MS (ESI+)m/z 499.1 (M+H)⁺.

Example 226 methyl((cis)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate

The geometric isomers of Example 224 were separated on reverse phaseHPLC (C18, CH₃CN/water (0.1% TFA), 5-40% gradient). Fractions of thesecond eluted isomer was collected and concentrated to provide the titlecompound (0.0046 g, 0.009 mmol, 6% yield). ¹H NMR (400 MHz, DMSO-d₆) δ11.47 (s, 1H), 7.69 (d, J=1.7 Hz, 1H), 7.49 (s, 1H), 7.30-7.23 (m, 2H),7.11 (d, J=2.5 Hz, 1H), 6.60 (s, 1H), 4.42 (s, 2H), 4.23 (s, 2H), 3.61(s, 3H), 3.51 (s, 3H), 2.89 (s, 3H), 2.87-2.79 (m, 2H), 1.72-1.26 (m,8H). MS (ESI+) m/z 499.1 (M+H)⁺.

Example 2272-(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)isoindoline-1,3-dione

Example 12d (0.06 g, 0.135 mmol) and3-(1,3-dioxoisoindolin-2-yl)propanal (0.082 g, 0.406 mmol) were combinedin tetrahydrofuran (1.353 mL) under nitrogen and treated drop-wise with1M titanium(IV) chloride in toluene (0.406 mL, 0.406 mmol). The reactionmixture was stirred for 18 hours at 60° C., cooled to ambienttemperature, and partitioned between ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloride, driedover anhydrous sodium sulfate, filtered and concentrated. Purificationby reverse phase HPLC (C18, CH₃CN/water (0.1% TFA), 0-100% gradient)provided the title compound. (0.018 g, 21%). ¹H NMR (500 MHz, DMSO-d₆) δ11.94 (d, J=2.14 Hz, 1H), 7.88 (d, J=1.53 Hz, 1H), 7.80-7.86 (m, 4H),7.72 (s, 1H), 7.31 (d, J=2.75 Hz, 1H), 7.28 (dd, J=8.09, 1.98 Hz, 1H),7.02-7.10 (m, 2H), 6.77-6.83 (m, 1H), 6.65-6.72 (m, 1H), 5.06-5.11 (m,1H), 4.40-4.57 (m, 2H), 3.70-3.79 (m, 1H), 3.65 (s, 3H), 3.54-3.63 (m,1H), 2.95 (s, 3H), 1.97-2.07 (m, 1H), 1.62 (dd, J=13.12, 5.19 Hz, 1H).MS (ESI+) m/z 629 (M+H)⁺.

Example 2284-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 12d (0.05 g, 0.113 mmol) and tetrahydropyran-4-carbaldehyde(0.064 g, 0.564 mmol) were combined in tetrahydrofuran (1.127 mL) undernitrogen and treated drop-wise with 1M titanium (IV) chloride in toluene(0.248 mL, 0.248 mmol). The reaction mixture was stirred for 24 hours at60° C., cooled to ambient temperature and partitioned between ethylacetate and water. The organic layer was washed with saturated aqueoussodium chloride, dried over anhydrous sodium sulfate, filtered andconcentrated. Purification by chromatography (silica gel, 30-60% of 3:1ethyl acetate/ethanol in heptanes) afforded the title compound (0.028 g,45%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.88 (d, J=1.22 Hz, 1H), 7.89 (d,J=1.83 Hz, 1H), 7.68 (s, 1H), 7.25 (dd, J=8.24, 1.83 Hz, 1H), 7.02-7.12(m, 3H), 6.72-6.85 (m, 2H), 4.68 (d, J=9.46 Hz, 1H), 4.49 (q, J=13.73Hz, 2H), 3.83 (d, J=11.60 Hz, 1H), 3.72 (d, J=9.77 Hz, 1H), 3.64 (s,3H), 2.91 (s, 3H), 2.81-2.98 (m, 2H), 1.97-2.02 (m, 1H), 1.48-1.60 (m,1H), 1.32 (t, J=8.70 Hz, 2H), 1.03 (d, J=9.16 Hz, 1H). MS (ESI+) m/z 540(M+H)⁺.

Example 229 benzyl(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)carbamate

Example 12d (0.05 g, 0.113 mmol) and3-[(benzyloxycarbonyl)amino]-1-propanal (0.070 g, 0.338 mmol) werecombined in tetrahydrofuran (1.127 mL) under nitrogen and treateddrop-wise with 1M titanium (IV) chloride in toluene (0.248 mL, 0.248mmol). The reaction mixture was stirred for 24 hours at 60° C., cooledto ambient temperature and partitioned between ethyl acetate and water.The organic layer was washed with saturated aqueous sodium chloride,dried over anhydrous sodium sulfate, filtered and concentrated.Purification by chromatography (silica gel, 30-60% of 3:1 ethylacetate/ethanol in heptanes) afforded the title compound (0.012 g, 17%).¹H NMR (500 MHz, DMSO-d₆) δ 11.88 (s, 1H), 7.83 (d, J=1.83 Hz, 1H), 7.68(s, 1H), 7.28-7.42 (m, 6H), 7.23 (d, J=7.93 Hz, 1H), 7.21 (d, J=2.44 Hz,1H), 7.08 (dd, J=12.66, 9.61 Hz, 1H), 6.95 (d, J=7.93 Hz, 1H), 6.81 (d,J=7.02 Hz, 2H), 5.06 (dd, J=9.16, 5.49 Hz, 1H), 5.03 (s, 2H) 4.40-4.54(m, 2H), 3.64 (s, 3H), 3.03-3.09 (m, 2H), 2.93 (s, 3H), 1.80-1.92 (m,1H), 1.30-1.39 (m, 1H). MS (ESI+) m/z 633 (M+H)⁺.

Example 2303-([1,1′-biphenyl]-2-yl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 230 was prepared according to the procedure used for thepreparation of Example 221, substituting [1,1′-biphenyl]-2-carbaldehydefor 2,6-dimethoxybenzaldehyde and 48 hours for the reaction time insteadof 24 hours, to provide the title compound (11 mg, 15%). ¹H NMR (500MHz, DMSO-d₆) δ 12.00 (d, J=2.3 Hz, 1H), 7.79 (d, J=1.9 Hz, 1H), 7.72(s, 1H), 7.64 (d, J=7.1 Hz, 2H), 7.52 (t, J=7.5 Hz, 2H), 7.46 (d, J=7.3Hz, 1H), 7.30 (s, 1H), 7.15-7.04 (m, 3H), 6.81-6.58 (m, 5H), 6.53-6.45(m, 1H), 6.00-5.85 (m, 1H), 4.48-4.34 (m, 2H), 3.64 (s, 3H), 2.73 (s,3H). MS (ESI+) m/z 608 (M+H)⁺.

Example 2314-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(quinolin-8-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 12d (53.2 mg, 0.120 mmol) and quinoline-8-carbaldehyde (94.0 mg,0.600 mmol) were combined in tetrahydrofuran (1 mL). To this suspensionwas added 1M titanium (IV) chloride in toluene (0.240 mL, 0.240 mmol).The reaction mixture was heated at 60° for 48 hours, cooled, dilutedwith water, the pH adjusted to 7 by the addition of saturated aqueoussodium bicarbonate, and extracted with ethyl acetate. The organic layerwas washed with saturated aqueous sodium chloride, dried with anhydroussodium sulfate, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 2-4% methanol in dichloromethane) toprovide the title compound (14 mg, 20%). ¹H NMR (500 MHz, DMSO-d₆) δ12.02 (s, 1H), 9.14 (dd, J=4.2, 1.7 Hz, 1H), 8.34 (dd, J=8.3, 1.7 Hz,1H), 8.21 (td, J=9.6, 6.2 Hz, 1H), 7.77-7.68 (m, 4H), 7.62 (dd, J=8.3,4.2 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.08 (t, J=7.7 Hz, 1H), 7.00 (td,J=8.1, 2.0 Hz, 1H), 6.93-6.84 (m, 2H), 6.71 (dd, J=8.1, 1.8 Hz, 1H),6.09 (d, J=8.1 Hz, 1H), 4.37-4.23 (m, 2H), 3.69 (s, 3H), 2.64 (s, 3H).MS (ESI+) m/z 583 (M+H)⁺.

Example 2324-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 12d (53.2 mg, 0.12 mmol) and picolinaldehyde (0.057 mL, 0.60mmol) were combined in tetrahydrofuran (1 mL). To this suspension wasadded 1M titanium(IV) chloride in toluene (0.240 mL, 0.240 mmol). Themixture was heated at 70° C. for 66 hours, cooled, diluted with water,the pH adjusted to 7 by the addition of saturated aqueous sodiumbicarbonate, and extracted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium chloride, dried with anhydroussodium sulfate, filtered, and concentrated. The residue was purified byflash chromatography (silica gel, 2-4% methanol in dichloromethane) toprovide the title compound (14 mg, 22%). ¹H NMR (500 MHz, DMSO-d₆) δ12.04 (d, J=1.8 Hz, 1H), 8.54-8.49 (m, 1H), 8.13 (td, J=9.4, 6.1 Hz,1H), 7.68 (s, 2H), 7.40 (td, J=7.7, 1.8 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H),7.15-6.99 (m, 3H), 6.91 (dd, J=8.3, 1.9 Hz, 1H), 6.67 (d, J=7.9 Hz, 1H),6.61 (s, 1H), 6.50 (d, J=8.2 Hz, 1H), 4.41-4.23 (m, 2H), 3.68 (s, 3H),2.69 (s, 3H). MS (ESI+) m/z 533 (M+H)⁺.

Example 23310-methyl-7-((methylsulfonyl)methyl)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 233a 5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

A mixture of 5-iodo-1H-indazole (1.02 g, 4.18 mmol) in tetrahydrofuran(20 mL) at 0° C. under argon was treated with sodium hydride (60% oildispersion, 0.192 g, 4.81 mmol). The reaction mixture was stirred at 0°C. for 15 minutes. (2-(chloromethoxy)ethyl)trimethylsilane (0.767 g,4.60 mmol) was added dropwise and the reaction mixture was stirred atambient temperature for 17 hours. The reaction mixture was partitionedbetween water and ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate twice. The combined organic layers were washedwith saturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified bychromatography on silica gel eluting with 10% ethyl acetate in heptaneto give the title compound (0.933 g, 2.49 mmol, 60% yield).

Example 233bN-(2-bromo-4-((methylsulfonyl)methyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-amine

A mixture of Example 233a (0.520 g, 1.389 mmol), Example 58g (0.367 g,1.389 mmol), cesium carbonate (0.905 g, 2.780 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos) (0.161 g,0.278 mmol), and palladium(II)acetate (0.031 g, 0.139 mmol) in dioxane(20 mL) under argon was heated in a sealed tube in a microwave reactorat 130° C. for 4 hours. The reaction mixture was cooled to ambienttemperature and partitioned between saturated sodium chloride solutionand ethyl acetate. The aqueous layer was extracted with additional ethylacetate. The combined organic layers were dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified bychromatography on silica gel eluting with 33% ethyl acetate in heptaneto give the title compound (0.170 g, 0.333 mmol, 24% yield).

Example 233c6-methyl-4-(5-((methylsulfonyl)methyl)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)amino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 233b (0.320 g, 0.627 mmol) and Example 1f (0.282 g,0.658 mmol) in dimethoxyethane (20 mL) and methanol (10 mL) under argonwas treated with cesium fluoride (0.286 g, 1.880 mmol) and palladiumtetrakis(triphenylphosphine) (0.72 g, 0.063 mmol). The reaction mixturewas stirred at 75° C. for 2 hours. The reaction mixture was cooled toambient temperature and excess 5N sodium hydroxide solution (8 mL) wasadded. The reaction mixture was stirred at ambient temperature for 2hours and then partitioned between aqueous ammonium chloride solutionand ethyl acetate. The aqueous layer was extracted with additional ethylacetate twice. The combined organic layers were washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flash columnchromatography on silica gel eluting with 1% methanol in dichloromethaneto afford the title compound (0.221 g, 0.381 mmol, 61% yield).

Example 233d10-methyl-7-((methylsulfonyl)methyl)-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 233c (0.221 g, 0.383 mmol) and paraformaldehyde(0.057 g, 1.913 mmol) in tetrahydrofuran (10 mL) under argon was treatedwith a 1M toluene solution of titanium tetrachloride (0.765 mL, 0.765mmol). The reaction mixture was stirred at ambient temperature for 3hours. The reaction mixture was quenched by the slow addition of excesssaturated sodium bicarbonate solution and partitioned between water andethyl acetate.

The aqueous layer was extracted with additional ethyl acetate followedby extraction with dichloromethane. The combined organic layers werewashed with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash column chromatography on silica gel eluting with 2% methanol indichloromethane to afford the title compound (0.120 g, 0.203 mmol, 53%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.79 (d, J=2.4 Hz, 1H), 7.91 (d,J=1.8 Hz, 1H), 7.74 (d, J=0.5 Hz, 1H), 7.58 (s, 1H), 7.44 (dd, J=8.0,1.9 Hz, 1H), 7.34 (dd, J=8.8, 4.0 Hz, 3H), 6.79 (dd, J=9.2, 2.2 Hz, 1H),6.57 (d, J=2.0 Hz, 1H), 5.52 (s, 2H), 4.67 (bs, 2H), 4.57 (s, 2H), 3.51(s, 3H), 3.41-3.36 (m, 2H), 3.00 (s, 3H), 0.74-0.68 (m, 2H), −0.15-−0.21(m, 9H). MS (ESI−) m/z 588.2 (M−H)⁻.

Example 2343-(4-(1H-imidazol-1-yl)phenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 234 was prepared according to the procedure used for thepreparation of Example 232, substituting4-(1H-imidazol-1-yl)benzaldehyde for picolinaldehyde and 48 hours forreaction time instead of 66 hours, to provide the title compound (8 mg,11%). ¹H NMR (500 MHz, DMSO-d₆) δ 12.09 (s, 1H), 8.11 (t, J=1.1 Hz, 1H),7.73 (d, J=1.8 Hz, 1H), 7.70 (s, 1H), 7.59 (t, J=1.3 Hz, 1H), 7.41 (d,J=8.7 Hz, 2H), 7.32 (d, J=1.7 Hz, 1H), 7.24-7.14 (m, 3H), 7.07-7.02 (m,2H), 6.91-6.80 (m, 3H), 6.50 (s, 1H), 4.44-4.27 (m, 2H), 3.67 (s, 3H),2.70 (s, 3H). MS (ESI+) m/z 598 (M+H)⁺.

Example 2354-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile

Example 235 was prepared according to the procedure used for thepreparation of Example 232, substituting 4-formylbenzonitrile forpicolinaldehyde and 48 hours for reaction time instead of 66 hours, toprovide the title compound (27 mg, 40%). ¹H NMR (500 MHz, DMSO-d₆) δ12.13 (s, 1H), 7.71 (d, J=9.8 Hz, 2H), 7.60 (d, J=8.2 Hz, 2H), 7.37-7.26(m, 3H), 7.23-7.15 (m, 1H), 7.05 (d, J=8.2 Hz, 1H), 6.90-6.78 (m, 3H),6.54 (s, 1H), 4.45-4.26 (m, 2H), 3.66 (s, 3H), 2.73 (s, 3H). MS (ESI+)m/z 557 (M+H)⁺.

Example 2364-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-(pyridin-2-yl)phenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 236 was prepared according to the procedure used for thepreparation of Example 232, substituting 3-(pyridin-2-yl)benzaldehydefor picolinaldehyde and 48 hours for reaction time instead of 66 hours,to provide the title compound (32 mg, 44%). ¹H NMR (500 MHz, DMSO-d₆) δ12.07 (d, J=2.3 Hz, 1H), 8.61-8.56 (m, 1H), 7.85-7.79 (m, 2H), 7.76-7.64(m, 4H), 7.34 (d, J=2.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.24 (t, J=7.7 Hz,1H), 7.21-7.13 (m, 2H), 7.03 (dd, J=8.2, 1.9 Hz, 1H), 6.94-6.81 (m, 3H),6.57 (s, 1H), 4.42-4.25 (m, 2H), 3.67 (s, 3H), 2.64 (s, 3H). MS (ESI+)m/z 609 (M+H)⁺.

Example 2373-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile

Example 237 was prepared according to the procedure used for thepreparation of Example 232, substituting 3-formylbenzonitrile forpicolinaldehyde and 48 hours for reaction time instead of 66 hours, toprovide the title compound (20 mg, 30%). ¹H NMR (500 MHz, DMSO-d₆) δ12.13 (s, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.71 (s, 1H), 7.55 (d, J=7.6 Hz,1H), 7.47-7.40 (m, 2H), 7.39-7.31 (m, 2H), 7.22-7.13 (m, 1H), 7.06 (dd,J=8.2, 1.9 Hz, 1H), 6.93-6.80 (m, 3H), 6.53 (s, 1H), 4.46-4.27 (m, 2H),3.66 (s, 3H), 2.72 (s, 3H). MS (ESI+) m/z 557 (M+H)⁺.

Example 2384-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 238a 1-(2,2-dimethoxyethyl)pyridin-2(1H)-one

A 20 mL microwave tube was charged with 2-hydroxypyridine (0.220 g,2.313 mmol), cesium carbonate (1.507 g, 4.63 mmol) and acetonitrile(11.57 mL) to give a white suspension. Bromoacetaldehyde dimethyl acetal(1.362 mL, 11.57 mmol) was added. The tube was sealed, and the reactionmixture was heated in a Biotage Creator at 120° C. for 30 minutes fixedhold time. The reaction mixture was partitioned between ethyl acetateand water. The organic layer was washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The reaction mixture was purified by flash chromatography(0-5% methanol:dichloromethane) to provide the title compound (0.210 g,50% yield).

Example 238b4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 238b was prepared according to the procedure used for thepreparation of Example 82, substituting Example 238a for methyl4-oxobutanoate, to provide the title compound as a white solid (0.0884g, 55% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.88-11.93 (m, 1H), 7.89 (d,J=2.0 Hz, 1H), 7.74 (s, 1H), 7.72-7.63 (m, 1H), 7.43 (ddd, J=8.9, 6.7,2.1 Hz, 1H), 7.21 (dd, J=8.2, 2.0 Hz, 1H), 7.00-7.11 (m, 2H), 6.82-6.89(m, 2H), 6.67 (d, J=2.6 Hz, 1H), 6.46 (d, J=9.1 Hz, 1H), 6.00 (td,J=6.6, 1.4 Hz, 1H), 5.50 (dd, J=9.1, 5.6 Hz, 1H), 4.54-4.36 (m, 3H),3.66 (s, 3H), 3.54-3.44 (m, 1H), 2.95 (s, 3H). MS (ESI+) m/z 563.0(M+H)⁺.

Example 239 ethyl4-(2,4-difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylateExample 239a4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid

A suspension of Example 208g (450 mg, 0.672 mmol) in 6 mLtetrahydrofuran was treated with 2N aqueous sodium hydroxide (2016 μL,4.03 mmol) and heated at 70° C. for 2 hours. Additional 2N sodiumhydroxide (2016 μL, 4.03 mmol) and 3 mL ethanol were added. The mixturewas heated at 70° C. for another 4 hours. The reaction mixture wasconcentrated. The residue was taken into water (10 mL), adjusted to pH 2and the precipitate was collected via filtration to give the titlecompound, which was used without further purification.

Example 239b4-(2-((2,4-difluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A solution of Example 239a (270 mg, 0.554 mmol) in 4 mL dichloromethanewas treated at 0° C. with 2 drops of dimethylformamide and oxalyldichloride (242 μL, 2.77 mmol). The mixture was stirred at ambienttemperature for 3 hours and then concentrated. The residue was takeninto 2 mL tetrahydrofuran and treated with ethylamine (2769 μL, 5.54mmol, 2.0 M solution in tetrahydrofuran) at 0° C. The mixture was thenstirred overnight. Water was added. The mixture was extracted with ethylacetate (3×) and partitioned. The combined organic layers were washedwith water (2×) and saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by column chromatography (silica gel, 0-8%methanol/dichloromethane gradient) to give the title compound (86 mg,0.167 mmol, 30% yield)

Example 239c ethyl4-(2,4-difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate

To a suspension of Example 239b (77 mg, 0.150 mmol) and ethyl2-oxoacetate (148 μL, 0.748 mmol, 50% solution in toluene) intetrahydrofuran (2 mL) at ambient temperature was added titanium(IV)chloride (1048 μL, 1.048 mmol, 1.0 M solution in toluene) The mixturewas stirred at ambient temperature under nitrogen for 40 hours. Thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with saturated aqueous sodium bicarbonate andsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was concentrated and the residue waspurified by column chromatography (silica gel, 0-8%methanol/dichloromethane gradient) to give the title compound (46 mg,0.077 mmol, 51% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.33 (s, 1H),8.41-8.21 (m, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.74 (s, 1H), 7.64 (td,J=9.4, 5.9 Hz, 1H), 7.20 (dd, J=8.3, 1.9 Hz, 1H), 7.17-7.04 (m, 2H),6.84 (d, J=8.2 Hz, 1H), 6.78 (s, 1H), 4.49 (d, J=13.7 Hz, 1H), 4.39 (d,J=13.7 Hz, 1H), 3.94 (ddd, J=14.3, 9.0, 5.4 Hz, 1H), 3.85 (dq, J=10.9,7.1 Hz, 1H), 3.69 (s, 3H), 3.26 (td, J=7.2, 3.7 Hz, 2H), 2.87 (s, 3H),1.13 (t, J=7.3 Hz, 3H), 0.86 (t, J=7.1 Hz, 3H). MS (ESI+) m/z 599.0(M+H)⁺.

Example 2404-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamideExample 240a methyl4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxylate

Example 206d (20 mg, 0.037 mmol) in methanol (20 mL) was added to[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.369 mg,1.871 μmol) and triethylamine (10.43 μL, 0.075 mmol) in a 50 mL pressurebottle. The mixture was pressurized with carbon monoxide (60 psi), andstirred 32 hours at 100° C. The solvent was removed. The reactionmixture was purified by flash chromatography (0-5%methanol:dichloromethane) to provide a white solid.

Example 240b4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxylicacid

A 250 mL round-bottomed flask was charged with Example 240a (0.108 g,0.210 mmol), lithium hydroxide (0.050 g, 2.103 mmol), tetrahydrofuran(3.00 mL), methanol (1.00 mL) and water (1.00 mL) to give a colorlesssolution. The reaction mixture was stirred at ambient temperature for120 hours. The reaction mixture was quenched with 1N HCl. The reactionmixture was filtered, and the solid was rinsed with water and dried in a60° C. vacuum oven overnight to provide the title compound as a tansolid (0.0695 g, 66% yield).

Example 240c4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonylchloride

A 25 mL round-bottomed flask was charged with Example 204b (0.0695 g,0.139 mmol) and dichloromethane (1.391 mL) to give a tan suspension.Oxalyl dichloride (0.018 mL, 0.209 mmol) and N,N-dimethylformamide(1.077 μL, 0.014 mmol) were added. The reaction mixture was stirred atambient temperature for 45 minutes. The solvent was removed,dichloromethane and toluene were added, and the solvent was evaporated.This was repeated 3× to provide a tan solid.

Example 240d4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide

A 25 mL round-bottomed flask was charged with Example 240c (0.024 g,0.046 mmol) and dichloromethane (0.463 mL) to give a tan solution.Ammonium hydroxide (0.027 mL, 0.695 mmol) was added, and the reactionmixture was stirred at ambient temperature for 2 hours. The reactionmixture was partitioned between dichloromethane and saturated aqueoussodium chloride. The organic layer was dried over anhydrous magnesiumsulfate, filtered, and concentrated. The reaction mixture was purifiedby reverse phase HPLC (Phenomenex Luna C8(2) 5 μm 100 Å AXIA column (30mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acidin water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A,0.5-7.0 min linear gradient 10-95% A, 7.0-10.0 min 95% A, 10.0-12.0 minlinear gradient 95-10% A). Samples were injected in 1.5 mL DMSO:methanol(1:1)) to provide a white solid (0.0010 g, 4% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 11.83 (s, 1H), 7.91 (m, 1H), 7.71 (s, 1H), 7.56 (s, 1H), 7.40(m, 1H), 7.36 (s, 1H), 7.20 (m, 1H), 6.92 (m, 1H), 6.61 (t, J=7.4 Hz,1H), 6.30 (dd, J=15.9, 9.4 Hz, 1H), 5.09 (d, J=16.7 Hz, 1H), 4.56 (m,3H), 3.60 (s, 6H), 3.01 (s, 6H). MS (ESI+) m/z 499.1 (M+H)⁺.

Example 241 4-(2,4-difluorophenyl)-N,10-dimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide

Example 241 was prepared according to the procedure used for thepreparation of Example 240d, substituting methylamine for ammoniumhydroxide, to provide the title compound as a white solid (0.0091 g, 38%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.83 (m, 1H), 7.96 (q, J=4.6 Hz,1H), 7.91 (d, J=2.0 Hz, 1H), 7.73 (s, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.18(d, J=2.6 Hz, 1H), 6.93 (m, 1H), 6.64 (td, J=8.6, 3.0 Hz, 1H), 6.38 (td,J=9.6, 5.8 Hz, 1H), 5.01 (m, 1H), 4.55 (m, 3H), 3.61 (s, 3H), 2.99 (s,3H), 2.62 (d, J=4.6 Hz, 3H). MS (ESI+) m/z 513.1 (M+H)⁺.

Example 242 4-(2,4-difluorophenyl)-N,N,10-trimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide

Example 242 was prepared according to the procedure used for thepreparation of Example 240d, substituting N,N-dimethylamine for ammoniumhydroxide, to provide the title compound as a white solid (0.0076 g, 31%yield). ¹H NMR (500 MHz, DMSO-d₆) δ 11.82 (s, 1H), 7.93 (d, J=5.9 Hz,1H), 7.75 (d, J=15.6 Hz, 1H), 7.18 (t, J=3.5 Hz, 1H), 7.21-7.11 (m, 2H),7.11-6.92 (m, 1H), 6.72 (s, 1H), 6.58 (s, 1H), 6.31 (s, 1H), 4.93 (dd,J=16.1, 10.8 Hz, 1H), 4.66-4.42 (m, 2H), 4.34 (d, J=16.5 Hz, 1H), 3.63(s, 4H), 2.98 (s, 3H), 2.88 (s, 3H), 2.72 (s, 2H), 2.22 (s, 2H). MS(ESI+) m/z 527.0 (M+H)⁺.

Example 243N-(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)acetamide

A mixture of Example 212 (0.062 g, 0.079 mmol) in dimethylformamide (5mL) was treated with N,N-diisopropylethylamine (0.062 mL, 0.356 mmol)and acetyl chloride (0.0062 g, 0.079 mmol) at ambient temperature underargon. The reaction mixture was stirred at ambient temperature for 2hours and then partitioned between aqueous ammonium chloride solutionand ethyl acetate. The aqueous layer was extracted 4 times withadditional ethyl acetate and then extracted three times withdichloromethane. The combined organic layers were dried over anhydrousmagnesium sulfate, filtered, and concentrated to afford the titlecompound (0.017 g, 0.035 mmol, 45% yield). ¹H NMR (400 MHz, DMSO-d₆) δ11.48 (s, 1H), 7.70 (s, 1H), 7.52-7.46 (m, 1H), 7.40-7.15 (m, 3H), 7.12(s, 1H), 4.45-4.38 (m, 2H), 4.22 (s, 2H), 3.68-3.54 (m, 3.5H), 3.44-3.35(m, 0.5H), 3.17-3.09 (m, 0.5H), 2.90-2.88 (m, 3H), 2.83-2.79 (m, 0.5H),1.81-1.44 (m, 5H), 1.30 (m, 4H), 1.06-0.86 (m, 2H). MS (ESI+) m/z 483.1(M+H)⁺.

Example 24410-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 244a6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-3-ylamino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A suspension of Example 5d (200 mg, 0.412 mmol), 3-bromopyridine (65.1mg, 0.412 mmol), cesium carbonate (335 mg, 1.030 mmol), anddicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (X-phos) (39.3mg, 0.082 mmol) in toluene (4 mL) and tert-butanol (1 mL) was purgedwith nitrogen and then heated in Biotage Initiator microwave oven at150° C. for 45 minutes. Water was added. The mixture was extracted withethyl acetate (3×). The combined organic layers were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, and filtered. The filtrate was concentrated and the residue waspurified by column chromatography (silica gel, 0-8%methanol/dichloromethane gradient) to give the title compound (74 mg,0.132 mmol, 31.9% yield).

Example 244b6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyridin-3-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 244a (55 mg, 0.098 mmol) and lithium hydroxide monohydrate(20.51 mg, 0.489 mmol) in dioxane (1.5 mL) and water (0.5 mL) wasstirred at 60° C. for 6 hours. The mixture was partitioned between waterand ethyl acetate. The aqueous layer was extracted with ethyl acetate(3×). The combined organic layers were washed with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by column chromatography (silicagel, 0-8% methanol/dichloromethane gradient) to give the title compound(33 mg, 0.081 mmol, 83% yield) as an off-white solid.

Example 244c10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A suspension of Example 244b (27 mg, 0.066 mmol) and paraformaldehyde(19.85 mg, 0.661 mmol) in acetic acid (1 mL) was stirred at 75° C. for1.5 hours. Acetic acid was evaporated under reduced pressure and theresidue was taken into dichloromethane and washed with 1N NaOH solution.The aqueous phase was back extracted with dichloromethane. The combinedorganic phases were dried over anhydrous magnesium sulfate, andfiltered. The filtrate was concentrated and the residue was purified bycolumn chromatography (silica gel, 0-8% methanol/dichloromethanegradient) to give the title compound (15 mg, 0.036 mmol, 54.0% yield) asa white solid. 1H NMR (500 MHz, DMSO-d₆) δ 11.88 (s, 1H), 7.94 (d, J=1.8Hz, 1H), 7.78 (d, J=2.9 Hz, 1H), 7.73 (dd, J=4.5, 1.1 Hz, 1H), 7.63 (s,1H), 7.47 (dd, J=8.0, 1.8 Hz, 1H), 7.38 (d, J=8.0 Hz, 2H), 6.97 (dd,J=8.5, 4.5 Hz, 1H), 6.82-6.76 (m, 1H), 5.24 (d, J=14.3 Hz, 1H), 4.52(dd, J=60.4, 26.1 Hz, 3H), 3.55 (s, 3H), 3.01 (s, 3H). MS ESI (+) 421.1(M+H)⁺.

Example 2454-(5-chloropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 245a4-(2-((5-chloropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 245a was prepared according to the procedure used for thepreparation of Example 244a, substituting 2-bromo-5-chloropyridine for3-bromopyridine to provide the title compound

Example 245b4-(2-((5-chloropyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 245b was prepared according to the procedure used for thepreparation of Example 244b, substituting example 245a for example 244ato provide the title compound

Example 245c4-(5-chloropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 245c was prepared according to the procedure used for thepreparation of Example 244c, substituting example 245b for example 244bto provide the title compound. 1H NMR (400 MHz, DMSO-d₆) δ 16.38-16.29(m, 1H), 11.86 (s, 1H), 7.95 (d, J=25.9 Hz, 2H), 7.64 (s, 1H), 7.49-7.27(m, 4H), 6.19 (d, J=8.3 Hz, 1H), 5.69 (d, J=15.8 Hz, 1H), 4.62 (d,J=13.5 Hz, 1H), 4.51 (d, J=13.5 Hz, 1H), 4.29 (d, J=15.6 Hz, 1H), 3.58(s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 455.1.

Example 2464-(1H-indazol-5-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 233d (0.058 g, 0.098 mmol) in dioxane (2 mL) atambient temperature under argon was treated with excess 4N HCl indioxane (7 mL). The reaction mixture was stirred at ambient temperaturefor 16 hours and then quenched with the slow addition of saturatedsodium bicarbonate solution until pH=8. The mixture was partitionedbetween aqueous sodium bicarbonate solution and ethyl acetate. Theaqueous layer was extracted with additional ethyl acetate. The combinedorganic layers were washed with saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate, filtered, and concentrated. Theresidue was purified by reverse phase HPLC (C18, CH₃CN/water (0.1% TFA),0-100% gradient) to afford the title compound as the trifluoroacetatesalt (0.024 g, 0.042 mmol, 43% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.79(s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.39 (dd, J=40.3, 7.9Hz, 3H), 7.18 (d, J=9.0 Hz, 1H), 6.72 (d, J=9.1 Hz, 1H), 6.62 (s, 1H),4.72 (s, 2H), 4.57 (s, 2H), 3.53 (s, 3H), 3.50 (bs, 1H), 3.01 (s, 3H).MS (ESI+) m/z 460.1 (M+H)⁺.

Example 2474-benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 5f (0.0515 g, 0.150 mmol) and benzaldehyde (0.0318g, 0.300 mmol) in dichloromethane (6 mL) was treated with acetic acid(0.086 mL, 1.500 mmol). The reaction mixture was stirred at 60° C. for 1hour then cooled to 0° C. (ice bath) and treated with sodiumtriacetoxyborohydride (0.0669 g, 0.300 mmol). The reaction mixture wasremoved from 0° C. ice bath and stirred at ambient temperature for 16hours. The reaction mixture was quenched by the slow addition ofsaturated sodium bicarbonate solution and then extracted twice withdichloromethane. The combined organic layers were washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified byrecrystallization from methanol and dimethylsulfoxide to afford thetitle compound (0.0145 g, 0.033 mmol, 22% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 11.80 (s, 1H), 7.71 (d, J=1.3 Hz, 1H), 7.56 (s, 1H),7.27-7.16 (m, 7H), 6.99 (d, J=2.2 Hz, 1H), 4.43 (s, 2H), 4.25 (s, 2H),4.05 (s, 2H), 3.65 (s, 3H), 2.93 (s, 3H). MS (ESI+) m/z 434.1 (M+H)⁺.

Example 24810-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 248a6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyrimidin-5-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 5d (0.300 g, 0.618 mmol), 5-iodopyrimidine (0.382g, 1.853 mmol), cesium carbonate (0.403 g, 1.236 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine(XPhos)(0.147 g, 0.309 mmol), and palladium (II) acetate (0.035 g, 0.154mmol) in toluene (12 mL) and tert-butanol (3 mL) under argon was heatedin a sealed tube in a microwave reactor at 160° C. for 1 hour. Thereaction mixture was cooled to ambient temperature and filtered throughfilter paper. The resulting filtrate was concentrated to near drynessand mixed with ethanol (10 mL), dioxane (20 mL), and excess 5N sodiumhydroxide solution (10 mL). The reaction mixture was stirred at ambienttemperature for 1 hour and then concentrated to 5 mL and partitionedbetween saturated ammonium chloride aqueous solution and ethyl acetate.The aqueous phase was extracted once more with ethyl acetate. Thecombined organic layers were washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash column chromatography onsilica gel eluting with 5% methanol in dichloromethane to afford thetitle compound (0.066 g, 0.161 mmol, 26% yield).

Example 248b10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 248a (0.040 g, 0.098 mmol) and paraformaldehyde(0.015 g, 0.488 mmol) in acetic acid (10 mL) under argon was stirred at75° C. for 2 hours. The reaction mixture was concentrated to asemi-solid and purified by reverse phase HPLC (C18, CH₃CN/water (0.1%TFA), 0-100% gradient) and dried under vacuum to afford the titlecompound (0.0065 g, 0.015 mmol, 15% yield). ¹H NMR (400 MHz, DMSO-d₆) δ11.59 (s, 1H), 8.31 (s, 1H), 7.95 (s, 3H), 7.59 (s, 1H), 7.51-7.46 (m,1H), 7.40-7.35 (m, 2H), 4.87 (s, 2H), 4.54 (s, 2H), 3.56 (s, 3H), 2.96(s, 3H). MS (ESI+) m/z 422.1 (M+H)⁺.

Example 24910-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 5f (208 mg, 0.606 mmol), picolinaldehyde (0.116 mL,1.211 mmol) and acetic acid (0.347 mL, 6.06 mmol) in dichloromethane (12mL) was heated under reflux, for 2 hours. The reaction mixture wascooled to ice/water bath temperature for 15 minutes and then sodiumtriacetoxyborohydride (297 mg, 1.333 mmol) was added to the reactionmixture under argon. The mixture was stirred at 0° C. for 15 minutes,allowed to warm slowly to ambient temperature over 2 hours, and thenstirred at ambient temperature for 16 hours. The pH of the mixture wasadjusted to pH=6-7 by the addition of saturated aqueous bicarbonatesolution, and the mixture was then extracted with dichloromethane. Theorganic layers were combined, dried over anhydrous magnesium sulfate,filter, and concentrated. The residue was triturated with methanol anddimethylsulfoxide, and the resulting solid was collected and dried toprovide the title compound (108 mg, 41% yield). ¹H NMR (500 MHz,DMSO-d₆) δ 11.80 (bs, 1H), 8.46 (ddd, J=4.8, 1.8, 0.9 Hz, 1H), 7.72 (d,J=1.9 Hz, 1H), 7.64 (td, J=7.6, 1.8 Hz, 1H), 7.56 (s, 1H), 7.29-7.15 (m,4H), 7.03 (d, J=2.5 Hz, 1H), 4.45-4.39 (m, 4H), 4.13 (s, 2H), 3.65 (s,3H), 2.92 (s, 3H). (ESI+) m/z 435.1 (M+H)⁺.

Example 25010-methyl-7-((methylsulfonyl)methyl)-4-(pyridazin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 250 was prepared according to the procedure used for thepreparation of Example 249, substituting pyridazine-3-carbaldehyde forpicolinaldehyde to provide the title compound. ¹H NMR (400 MHz, DMSO-d₆)δ 11.82 (bs, 1H), 9.08 (dd, J=4.7, 1.8 Hz, 1H), 7.73 (d, J=1.9 Hz, 1H),7.62-7.51 (m, 3H), 7.30-7.19 (m, 2H), 7.03 (d, J=2.6 Hz, 1H), 4.56 (s,2H), 4.43 (s, 2H), 4.15 (s, 2H), 3.65 (s, 3H), 2.92 (s, 3H). (ESI+) m/z436.4 (M+H)⁺.

Example 251(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Preparatory chiral SFC separation of the product from Example 238(0.0204 g) on a WHELK-O S.S column. (21×250 mm, 5 micron column, elutingwith 30% methanol in supercritical CO₂ at 70 mL/min for 20 minutes)afforded the title compound as the first eluted peak. Thestereochemistry was randomly assigned to this first eluted peak (8.6 mg,84% recovery). 1H NMR (500 MHz, DMSO-d₆) δ 11.90 (bs, 1H), 7.89 (d,J=2.0 Hz, 1H), 7.74 (s, 1H), 7.64-7.72 (m, 1H), 7.43 (ddd, J=8.9, 6.7,2.1 Hz, 1H), 7.21 (dd, J=8.2, 2.0 Hz, 1H), 7.00-7.11 (m, 2H), 6.82-6.89(m, 2H), 6.67 (s, 1H), 6.46 (dd, J=9.1, 1.3 Hz, 1H), 6.00 (td, J=6.6,1.4 Hz, 1H), 5.50 (dd, J=9.1, 5.6 Hz, 1H), 4.37-4.55 (m, 3H), 3.66 (s,3H), 3.44-3.54 (m, 1H), 2.95 (s, 3H). MS (ESI+) m/z 563.1 (M+H)⁺.

Example 252(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Preparatory chiral SFC separation of the product from Example 238(0.0204 g) on a WHELK-O S.S column. (21×250 mm, 5 micron column, elutingwith 30% methanol in supercritical CO₂ at 70 mL/min for 20 minutes)afforded the title compound as the second eluted peak. Thestereochemistry was randomly assigned to this second eluted peak (7.9mg, 77% recovery). 1H NMR (500 MHz, DMSO-d₆) δ 11.90 (bs, 1H), 7.89 (d,J=2.0 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J=6.3 Hz, 1H), 7.43 (ddd, J=8.9,6.7, 2.1 Hz, 1H), 7.21 (dd, J=8.2, 2.0 Hz, 1H), 7.00-7.11 (m, 2H),6.82-6.89 (m, 2H), 6.67 (s, 1H), 6.46 (d, J=9.1 Hz, 1H), 6.00 (td,J=6.6, 1.3 Hz, 1H), 5.50 (dd, J=9.1, 5.6 Hz, 1H), 4.36-4.55 (m, 3H),3.66 (s, 3H), 3.44-3.51 (m, 1H), 2.95 (s, 3H). MS (ESI+) m/z 563.1(M+H)⁺.

Example 25310-methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 253a6-methyl-4-(5-((methylsulfonyl)methyl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 207a (0.16 g, 0.33 mmol), 2-bromo-5-(trifluoromethyl)pyridine(0.112 g, 0.495 mmol), diacetoxypalladium (0.019 g, 0.083 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.079g, 0.165 mmol) and cesium carbonate (0.215 g, 0.66 mmol) were combinedin a 20-mL microwave vial and sparged with nitrogen for 30 minutes. Tothis were added nitrogen-sparged anhydrous toluene (2.4 mL) andtert-butanol (0.6 mL). The reaction mixture was heated at 105° C.overnight, then cooled to ambient temperature and partitioned betweenethyl acetate and water. The organic layer was washed with brine,treated with 3-mercaptopropyl-functionalized silica gel for 20 minutes,dried over anhydrous magnesium sulfate, filtered through a plug ofCelite and concentrated. The residue was purified by flashchromatography (silica gel, 25-100% ethyl acetate in dichloromethane,then 5-15% methanol in dichloromethane) to give 0.077 g (37%) of thetitle compound and 0.0245 g (16%) of Example 253b.

Example 253b6-methyl-4-(5-((methylsulfonyl)methyl)-2-((5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 253a (0.077 g, 0.122 mmol) in tetrahydrofuran (1.5mL) was treated with tetrabutylammonium fluoride (0.028 g, 0.107 mmol),heated at 50° C. for 50 minutes and then at 60° C. for one hour. It wasthen stirred at ambient temperature overnight.

Additional tetrabutylammonium fluoride (0.028 g, 0.107 mmol) was addedand heating was continued at 60° C. for 3 hours. The reaction mixturewas concentrated to dryness, triturated with ethyl acetate and thendried in a vacuum oven at 70° C. to give 0.054 g (93%) of the titlecompound.

Example 253c10-methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stirbar were addedExample 253b (0.025 g, 0.052 mmol), paraformaldehyde (0.006 g, 0.207mmol), and acetic acid (1.2 mL). The vial was capped and heated at 75°C. for 45 minutes. Additional paraformaldehyde (0.006 g, 0.207 mmol) wasadded and heating was continued for 1 hour at 75° C. The reactionmixture was then concentrated. The residue was dissolved in acetonitrile(3 mL) and water (0.75 mL), treated with sodium acetate (0.043 g, 0.518mmol) and heated at 50° C. for 1 hour. The reaction mixture was cooledto ambient temperature, partitioned between ethyl acetate and water,washed with brine, dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, 0-8% methanol in dichloromethane) to give 0.026 g (103%) of thetitle compound. ¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (s, 1H), 8.33 (s, 1H),7.95 (s, 1H), 7.67 (s, 1H), 7.62 (d, J=7.63 Hz, 1H), 7.44 (m, 2H), 7.34(s, 1H), 6.29 (s, 1H), 5.83 (s, 1H), 4.64 (m, 1H), 4.53 (m, 1H), 4.35(d, J=14.95 Hz, 1H), 3.58 (s, 3H), 3.02 (s, 3H). MS (ESI+) m/z 489.1(M+H)⁺.

Example 2544-(2-fluoropyridin-4-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 254a

A mixture of Example 207a (0.146 g, 0.3 mmol), 4-bromo-2-fluoropyridine(0.069 g, 0.390 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (0.072 g, 0.150mmol), palladium(II) acetate (0.017 g, 0.075 mmol), and cesium carbonate(0.244 g, 0.750 mmol) in toluene (3 mL) and tert-butanol (0.750 mL) washeated at 160° C. for 1 hour. Two more identical runs were conducted,and the combined reaction mixtures were partitioned between water andethyl acetate. The aqueous layer was extracted with additional ethylacetate several times. The combined organic layers were washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by flashchromatography on silica gel eluting with 100:10:1 ethylacetate/methanol/NH₄OH to afford 0.14 g (36%) of the title compound.

Example 254b4-(2-fluoropyridin-4-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 254a (0.13 g, 0.305 mmol) and paraformaldehyde(0.027 g, 0.914 mmol) in acetic acid (6 mL) was heated at 75° C. for 4hours. The solvent was evaporated, and the residue was purified byreverse phase preparative HPLC (C18, CH₃CN/water (0.1% trifluoroaceticacid), 0-100% gradient) to afford the title compound as trifluoroaceticacid salt (0.085 g, 0.154 mmol, 50.5% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 11.94 (s, 1H), 7.96 (d, J=1.9 Hz, 1H), 7.65 (d, J=17.7 Hz, 2H),7.55-7.34 (m, 4H), 5.27 (d, J=16.3 Hz, 1H), 4.64 (d, J=13.6 Hz, 1H),4.60-4.46 (m, 2H), 3.57 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 438.9[M+H]⁺.

Example 25510-methyl-4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 255 was prepared according to the procedure used for thepreparation of Example 249, substituting1-methyl-1H-pyrazole-3-carbaldehyde for picolinaldehyde, and the residuewas recrystallized from dichloromethane, to provide the title compound.¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (bs, 1H), 7.69 (d, J=2.0 Hz, 1H),7.54-7.48 (m, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.23 (dd, J=8.2, 2.0 Hz, 1H),7.15-6.97 (m, 1H), 5.96 (d, J=2.1 Hz, 1H), 4.43 (bs, 2H), 4.23-4.04 (m,4H), 3.75 (s, 2H), 3.63 (s, 3H), 2.92 (s, 3H). (ESI+) m/z 438.1 (M+H)⁺.

Example 2564-(6-methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 256a4-(2-((6-methoxypyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 207a (0.243 g, 0.5 mmol), 2-bromo-6-methoxypyridine (0.188 g, 1mmol), diacetoxypalladium (0.028 g, 0.125 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.12g, 0.25 mmol), and cesium carbonate (0.326 g, 1 mmol) were combined in a5-mL microwave vial. Anhydrous toluene (4 mL) and tert-butanol (1 mL)were added. The vial was capped and the mixture was heated at 160° C.for 1 hour in a Biotage microwave reactor. The reaction mixture wasfiltered through a fritted funnel to remove the palladium solids. Thefiltrate was partitioned between ethyl acetate and water. The organiclayer was washed with saturated aqueous sodium chloride, treated with3-mercaptopropyl-functionalized silica gel for 20 minutes, dried overanhydrous magnesium sulfate, filtered through a plug of Celite, andconcentrated. The residue was purified by flash chromatography (silicagel, 0-100% ethyl acetate in dichloromethane, then 5-10% methanol inethyl acetate) to give 0.15 g (51%) of the title compound and 0.08 g(37%) of Example 256b.

Example 256b4-(2-((6-methoxypyridin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 256a (0.122 g, 0.206 mmol) and tetrabutylammoniumfluoride (0.108 g, 0.412 mmol) in tetrahydrofuran (3.5 mL) was heated at60° C. for 50 minutes and then concentrated. The residue was purified byflash chromatography (silica gel, 0-20% methanol in dichloromethane) andtrituration in dichloromethane to give 0.077 g (71%) of the titlecompound. A portion of this material was then combined with a portion ofthe deprotected material obtained in Example 256a (0.133 g total) andpurified by reverse phase HPLC (C18, acetonitrile/water (0.1%trifluoroacetic acid), 5-70%) to provide 0.071 g (43% recovery) of thetitle compound as the trifluoroacetic acid salt.

Example 256c4-(6-methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 256b (0.043 g, 0.077 mmol) and paraformaldehyde(0.005 g, 0.155 mmol) were combined in a 5-mL microwave vial. The vialwas capped and the mixture was sparged with nitrogen for 30 minutes. Tothis was added nitrogen-sparged acetic acid (3 mL). The resultingmixture was stirred at ambient temperature for 4 hours. The reactionmixture was then quenched with methanol and concentrated to drynesskeeping the bath temperature below 30° C. The residue was purified byreverse phase HPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid),5-75%) to provide 0.019 g (43%) of the title compound as thetrifluoroacetic acid salt. ¹H NMR (400 MHz, DMSO-d₆) δ 11.85 (d, J=1.83Hz, 1H), 7.93 (d, J=1.53 Hz, 1H), 7.64 (s, 1H), 7.44 (m, 1H), 7.39 (m,1H), 7.31 (d, J=2.44 Hz, 1H), 7.17 (t, J=7.93 Hz, 1H), 5.90 (d, J=7.63Hz, 1H), 5.78 (d, J=15.56 Hz, 1H), 5.58 (d, J=7.93 Hz, 1H), 4.62 (m,1H), 4.52 (m, 1H), 4.22 (d, J=15.26 Hz, 1H), 3.74 (s, 3H), 3.58 (s, 3H),2.99 (m, 3H). MS (ESI+) m/z 451.1 (M+H)⁺.

Example 2574-(2,2-dimethyl-3-morpholinopropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 257a4-(2-((2,2-dimethyl-3-morpholinopropyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 5d (77 mg, 0.159 mmol) and2,2-dimethyl-3-morpholinopropanal (0.056 mL, 0.317 mmol) was stirred indichloromethane (5 mL). To this mixture was added acetic acid (0.045 mL,0.793 mmol). The resulting partial suspension was heated under refluxfor 1.5 hour. The reaction mixture was cooled in an ice/water bath for15 minutes and then sodium triacetoxyborohydride (106 mg, 0.476 mmol)was added to the mixture under argon. The mixture was stirred at 0° C.for 15 minutes and then allowed to warm slowly to ambient temperatureover 1 hour. The mixture was then stirred at ambient temperature for 16hours. Saturated aqueous sodium bicarbonate solution was added followedby addition of saturated aqueous ammonium chloride and water. Themixture was extracted with dichloromethane and the layers separated. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated to provide the title compound.

Example 257b4-(2-((2,2-dimethyl-3-morpholinopropyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 257a (130 mg, 0.203 mmol) was dissolved in dioxane (8 mL) andethanol (4 mL). To this mixture was added 5N aqueous sodium hydroxidesolution (5 mL) and the mixture was stirred at ambient temperature for 4hours. The mixture was concentrated to approximately ⅓ of the volume andthen partitioned between saturated aqueous ammonium chloride and ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was triturated with a mixture ofethyl ether and ethyl acetate, filtered, and dried, to provide the titlecompound.

Example 257c4-(2,2-dimethyl-3-morpholinopropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 257b (38 mg, 0.077 mmol) and paraformaldehyde (12.5mg, 0.411 mmol) in tetrahydrofuran (10 mL) was stirred at ambienttemperature. To resulting suspension was added 1M solution of titaniumtetrachloride (0.82 mL). The reaction mixture was stirred for 24 hoursat ambient temperature and then added to a mixture of saturated aqueoussodium bicarbonate and ethyl acetate. The organic layer was separatedand the aqueous layer extracted with ethyl acetate. The combined organiclayers were dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 2% methanol/dichloromethane) to provide the title compound (10.8mg, 28% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (bs, 1H), 7.63 (d,J=2.1 Hz, 1H), 7.51 (s, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.24 (dd, J=8.2,2.0 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 4.42 (s, 2H), 4.13 (s, 2H), 3.63(s, 3H), 3.37 (m, 4H), 2.91 (s, 3H), 2.13 (bs, 4H), 1.88 (bs, 2H), 0.63(s, 6H). (ESI+) m/z 499.2 (M+H)⁺.

Example 2584-(5-fluoropyrimidin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 258a4-(2-((5-fluoropyrimidin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 207a (0.243 g, 0.5 mmol), 2-bromo-5-fluoropyrimidine (0.177 g, 1mmol), diacetoxypalladium (0.028 g, 0.125 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.12g, 0.25 mmol), and cesium carbonate (0.326 g, 1 mmol) were combined in a5-mL microwave vial and sparged with nitrogen for 30 minutes. Anitrogen-sparged solution of anhydrous toluene (3.2 mL) and tert-butanol(0.8 mL) was added. The reaction mixture was heated at 110° C. for 3hours, cooled to ambient temperature, and filtered through a frittedfunnel to remove the palladium solids. The filtrate was partitionedbetween ethyl acetate and water. The organic layer was washed withsaturated aqueous sodium chloride, treated with3-mercaptopropyl-functionalized silica gel for 20 minutes, dried overanhydrous magnesium sulfate, filtered through a plug of Celite, andconcentrated. The residue was triturated with methanol, filtered, anddried in a vacuum oven at 70° C. to give 0.215 (74%) of the titlecompound.

Example 258b4-(2-((5-fluoropyrimidin-2-yl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 258a (0.215 g, 0.37 mmol) in tetrahydrofuran (15mL) was treated with tetrabutylammonium fluoride (0.145 g, 0.554 mmol)and stirred at 60° C. for 1 hour and 40 minutes. The reaction mixturewas cooled to ambient temperature and concentrated. The concentrate wasslurried in dichloromethane and the solid was collected by filtrationand dried in a vacuum oven at 70° C. to give 0.068 g (43%) of the titlecompound.

Example 258c4-(5-fluoropyrimidin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 258b (0.059 g, 0.137 mmol) and paraformaldehyde(0.016 g, 0.548 mmol) were combined in a 5-mL microwave vial. The vialwas capped and sparged with nitrogen for 30 minutes. Nitrogen-spargedacetic acid (5 mL) was added and the mixture was heated at 75° C. for 3hours and 40 minutes. The reaction mixture was concentrated to dryness,slurried in water and treated with sodium acetate until basic. Theresulting mixture was heated at 50° C. for 2 hours and then cooled toambient temperature. The solid was collected by filtration, rinsed with300 mL of water and dried in a vacuum oven at 70° C. overnight. Thesolid was then slurried in ethyl acetate, stirred for 1 hour andfiltered. To this solid (0.04 g, 0.091 mmol) in methanol (0.25 mL) wasadded hydrogen chloride solution (4 M in 1,4-dioxane) (0.3 mL, 1 mmol).The resulting mixture was stirred at ambient temperature for 30 minutes.The solid was collected by filtration and dried in a vacuum oven at 70°C. to give 0.0354 (54%) of the title compound as the HCl salt. ¹H NMR(400 MHz, DMSO-d₆) δ 11.87 (d, J=2.14 Hz, 1H), 8.31 (s, 2H), 7.83 (d,J=1.53 Hz, 1H), 7.60 (s, 1H), 7.37 (m, 2H), 7.30 (d, J=2.44 Hz, 1H),5.70 (d, J=15.56 Hz, 1H), 4.60 (m, 1H), 4.49 (m, 1H), 4.34 (d, J=15.56Hz, 1H), 3.58 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 440.1 (M+H)⁺.

Example 25910-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 259a6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyrimidin-4-ylamino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 207a (0.243 g, 0.5 mmol), 4-bromopyrimidine (0.159 g, 1 mmol),diacetoxypalladium (0.028 g, 0.125 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.12g, 0.25 mmol), and cesium carbonate (0.326 g, 1 mmol) were combined in a5-mL microwave vial and sparged with nitrogen for 30 minutes. Anitrogen-sparged solution of anhydrous toluene (3.2 mL) and tert-butanol(0.8 mL) was added. The reaction mixture was heated at 110° C. for 16.5hours, cooled to ambient temperature and filtered through a frittedfunnel to remove the palladium solids. The filtrate was partitionedbetween ethyl acetate and water. The organic layer was washed withsaturated aqueous sodium chloride, treated with3-mercaptopropyl-functionalized silica gel for 20 minutes, dried overanhydrous magnesium sulfate, filtered through a plug of Celite, andconcentrated. The residue was purified by flash chromatography (silicagel, 20 to 100% of a 3:1 mixture of ethyl acetate/ethanol in heptanes)to provide an impure mixture. The material was subjected to a secondflash chromatography (silica gel, 45 to 50% of a 3:1 mixture of ethylacetate/ethanol in heptanes) to provide 0.042 g (15%) of the titlecompound.

Example 259b6-methyl-4-(5-((methylsulfonyl)methyl)-2-(pyrimidin-4-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 259a (0.042 g, 0.075 mmol) in tetrahydrofuran (2mL) was treated with tetrabutylammonium fluoride (0.02 g, 0.075 mmol)and heated at 60° C. for 45 minutes. Additional tetrabutylammoniumfluoride (0.02 g, 0.075 mmol) was added and heating was continued foranother 1.25 hours. The reaction mixture was cooled to ambienttemperature, concentrated, and slurried in ethyl acetate. The solid wascollected by filtration and then purified by reverse phase HPLC (C18,acetonitrile/water (0.1% trifluoroacetic acid), 5-70%) to provide 0.039g (99%) of the title compound.

Example 259c10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stirbar were addedExample 259b (0.039 g, 0.075 mmol), paraformaldehyde (0.011 g, 0.375mmol) and acetic acid (1.3 mL). The vial was capped and heated at 75° C.for 40 minutes. The reaction mixture was concentrated. The residue wasdissolved in acetonitrile (3 mL) and water (0.75 mL) and treated withsodium acetate until basic. The resulting mixture was heated at 50° C.for one hour and then cooled to ambient temperature. The reactionmixture was partitioned between ethyl acetate and water, washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated. The residue was purified by reversephase HPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid), 10-60%)to provide 0.004 g (9%) of the title compound as the trifluoroaceticacid salt. ¹H NMR (500 MHz, DMSO-d₆) δ 11.87 (d, J=0.61 Hz, 1H), 8.24(m, 2H), 7.82 (s, 1H), 7.60 (s, 1H), 7.35 (m, 3H), 6.60 (t, J=4.73 Hz,1H), 5.79 (d, J=15.56 Hz, 1H), 4.60 (m, 1H), 4.49 (d, J=13.43 Hz, 1H),4.30 (d, J=15.26 Hz, 1H), 3.58 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z422.1 (M+H)⁺.

Example 2604-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 260a4-(2-((2-(3-(dimethylamino)propoxy)benzyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 5d (106 mg, 0.218 mmol) and2-(3-(dimethylamino)propoxy)benzaldehyde (0.067 mL, 0.314 mmol) wasstirred in dichloroethane (5 mL). To this mixture was added acetic acid(0.062 mL, 1.091 mmol). The resulting partial suspension was heatedunder reflux for 1.5 hour. The reaction mixture was cooled in anice/water bath for 15 minutes and then sodium triacetoxyborohydride (146mg, 0.655 mmol) was added to the mixture under argon. The mixture wasstirred at 0° C. for 15 minutes and then allowed to warm slowly toambient temperature over 1 hour. The mixture was then stirred at ambienttemperature for 16 hours. Saturated aqueous sodium bicarbonate solutionwas added followed by saturated aqueous sodium carbonate and water. Themixture was extracted with dichloromethane and the layers separated. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 4-10% methanol in dichloromethane) to provide the title compound.

Example 260b4-(2-((2-(3-(dimethylamino)propoxy)benzyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 260a (101 mg, 0.149 mmol) was dissolved in dioxane (5 mL). Tothis mixture was added 5N aqueous sodium hydroxide solution (5 mL) andthe mixture was stirred at 80° C. for 4 hours. The mixture waspartitioned between saturated aqueous ammonium chloride and ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 10% methanol in dichloromethane) to providethe title compound.

Example 260c4-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 260b (43 mg, 0.082 mmol) and paraformaldehyde (10mg, 0.329 mmol) in tetrahydrofuran (10 mL) was stirred at ambienttemperature. To resulting suspension was added 1M solution of titaniumtetrachloride (0.66 mL). The reaction mixture was stirred for 24 hoursat ambient temperature and then added to a mixture of saturated aqueoussodium bicarbonate and ethyl acetate. The organic layer was separatedand the aqueous layer extracted with ethyl acetate. The combined organiclayers were dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by reverse phase HPLC (C18,CH₃CN/water (0.1% trifluoroacetic acid), 0-100% gradient) to afford thetitle compound (16.5 mg, 38%) as the trifluoroacetic acid salt. ¹H NMR(400 MHz, DMSO-d₆) δ 11.83 (s, 1H), 9.41 (s, 1H), 7.74 (s, 1H), 7.57 (s,1H), 7.25-7.15 (m, 3H), 7.11 (d, J=7.3 Hz, 1H), 7.06 (d, J=2.7 Hz, 1H),6.95 (d, J=8.2 Hz, 1H), 6.83 (t, J=7.4 Hz, 1H), 4.44 (s, 2H), 4.25 (s,2H), 4.12 (s, 2H), 4.00 (t, J=5.9 Hz, 2H), 3.57 (s, 3H), 3.16 (dt,J=9.7, 5.3 Hz, 2H), 2.94 (s, 3H), 2.77 (d, J=4.5 Hz, 6H), 2.05 (dq,J=11.6, 5.9 Hz, 2H). (ESI+) m/z 535.1 (M+H)⁺.

Example 2612-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)-2-phenylacetonitrile

A mixture of Example 5f (57.7 mg, 0.168 mmol), benzaldehyde (19.6 mg,0.185 mmol), and sodium cyanide (9.3 mg, 0.185 mmol) in methanol (8 mL)was heated to 60° C. over 30 minutes. Acetic acid (0.481 mL, 8.40 mmol)was added, and the partial suspension was heated at 60° C. for 18 hours.To the cooled reaction mixture was added water (10 mL) and the resultingprecipitate collected by filtration. The precipitate was purified byreverse phase HPLC (C18, CH₃CN/water (0.1% trifluoroacetic acid), 0-100%gradient) to afford the title compound (20 mg, 26%). ¹H NMR (400 MHz,90° C., DMSO-d₆) δ 11.53 (s, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.54 (s, 1H),7.31 (d, J=12.7 Hz, 7H), 6.93 (d, J=2.7 Hz, 1H), 5.64 (s, 1H), 4.43 (d,J=1.6 Hz, 2H), 4.19 (s, 2H), 3.64 (s, 3H), 2.88 (s, 3H). (ESI+) m/z459.1 (M+H)⁺.

Example 2622-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)phenoxy)acetamideExample 262a2-(2-(((2-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((methylsulfonyl)methyl)phenyl)amino)methyl)phenoxy)acetamide

A mixture of Example 5d (260 mg, 0.536 mmol) and2-(2-formylphenoxy)acetamide (80 mg, 0.446 mmol) was stirred indichloroethane (7 mL). To this mixture was added acetic acid (0.128 mL,2.232 mmol). The resulting partial suspension was heated at 80° C. for2.5 hours. The reaction mixture was cooled in an ice/water bath for 15minutes and then sodium triacetoxyborohydride (299 mg, 1.34 mmol) wasadded to the mixture under argon. The mixture was stirred at 0° C. for15 minutes and then allowed to warm slowly to ambient temperature over 1hour. The mixture was then stirred at ambient temperature for 16 hours.Saturated aqueous sodium bicarbonate solution was added followed byaddition of water. The mixture was extracted with dichloromethane andthe layers separated. The organic layer was dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was purifiedby flash chromatography (silica gel, 1-3% methanol in dichloromethane)to provide the title compound.

Example 262b2-(2-(((2-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-((methylsulfonyl)methyl)phenyl)amino)methyl)phenoxy)acetamide

Example 262a (170 mg, 0.262 mmol) was dissolved in dioxane (10 mL). Tothis mixture was added 5N aqueous sodium hydroxide solution (3 mL) andthe mixture was stirred at 80° C. for 6 hours. The mixture waspartitioned between saturated aqueous ammonium chloride and ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated to provide the title compound.

Example 262c2-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)phenoxy)acetamide

A mixture of Example 262b (49 mg, 0.099 mmol) and paraformaldehyde (12mg, 0.396 mmol) in tetrahydrofuran (10 mL) was stirred at ambienttemperature. To the resulting suspension was added a 1M solution oftitanium tetrachloride (0.79 mL). The reaction mixture was stirred for16 hours at ambient temperature and then added to a mixture of saturatedaqueous sodium bicarbonate and ethyl acetate. The organic layer wasseparated and the aqueous layer extracted with ethyl acetate. Thecombined organic layers were dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by reverse phaseHPLC (C18, CH₃CN/water (0.1% trifluoroacetic acid), 0-70% gradient) toafford the title compound (3.4 mg, 7%)¹H NMR (400 MHz, DMSO-d₆) δ 11.51(s, 1H), 7.73 (s, 1H), 7.52 (s, 1H), 7.21 (s, 2H), 7.16 (t, J=7.9 Hz,1H), 7.12-6.96 (m, 4H), 6.89 (d, J=8.3 Hz, 1H), 6.81 (t, J=7.4 Hz, 1H),4.41 (d, J=5.6 Hz, 4H), 4.28 (s, 2H), 4.17 (s, 2H), 3.65 (s, 3H), 2.89(s, 3H). (ESI+) m/z 507.2 (M+H)⁺.

Example 2634-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylicacid

The preparation of Example 263 was described in Example 209a. ¹H NMR(500 MHz, DMSO-d₆) δ 13.21 (s, 1H), 12.44 (s, 1H), 7.83 (d, J=1.22 Hz,1H), 7.71 (s, 1H), 7.28 (dd, J=8.24, 1.53 Hz, 1H), 7.10 (m, 1H), 7.01(d, J=7.93 Hz, 1H), 6.88 (td, J=8.54, 2.44 Hz, 1H), 6.82 (td, J=9.23,5.95 Hz, 1H), 5.09 (s, 2H), 4.49 (s, 2H), 3.63 (s, 3H), 2.96 (s, 3H). MS(ESI+) m/z 500.1 (M+H)⁺.

Example 26410-methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)benzyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 264a6-methyl-4-(5-((methylsulfonyl)methyl)-2-((2-(pyridin-2-ylmethoxy)benzyl)amino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 5d (72.4 mg, 0.149 mmol) and2-(pyridin-2-ylmethoxy)benzaldehyde (0.027 mL, 0.124 mmol) was stirredin dichloroethane (5 mL). To this mixture was added acetic acid (0.036mL, 0.621 mmol). The resulting partial suspension was heated at 80° C.for 2.5 hour. The reaction mixture was cooled in an ice/water bath for15 minutes and then sodium triacetoxyborohydride (83 mg, 0.373 mmol) wasadded to the mixture under argon. The mixture was stirred at 0° C. for15 minutes and then allowed to warm slowly to ambient temperature over 1hour. The mixture was then stirred at ambient temperature for 18 hours.Saturated aqueous sodium bicarbonate solution was added followed by theaddition of water. The mixture was extracted with dichloromethane andthe layers separated. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash chromatography (silica gel, 1-2% methanol in dichloromethane)to provide the title compound.

Example 264b6-methyl-4-(5-((methylsulfonyl)methyl)-2-((2-(pyridin-2-ylmethoxy)benzyl)amino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 264a (90 mg, 0.132 mmol) was dissolved in dioxane (8 mL). Tothis mixture was added 5N aqueous sodium hydroxide solution (2 mL) andthe mixture was stirred at 85° C. for 4 hours. The mixture waspartitioned between saturated aqueous ammonium chloride and ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated to provide the title compound.

Example 264c10-methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)benzyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 264b (44 mg, 0.083 mmol) and paraformaldehyde (10mg, 0.333 mmol) in tetrahydrofuran (10 mL) was stirred at ambienttemperature. To resulting suspension was added a 1M solution of titaniumtetrachloride (0.67 mL). The reaction mixture was stirred for 7 hours atambient temperature and then added to a mixture of saturated aqueoussodium bicarbonate and ethyl acetate. The organic layer was separatedand the aqueous layer extracted with ethyl acetate. The combined organiclayers were dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by reverse phase HPLC (C18,CH₃CN/water (0.1% trifluoroacetic acid), 0-100% gradient) to afford thetitle compound (19.7 mg, 44%)¹H NMR (500 MHz, DMSO-d₆) δ 11.97 (d, J=2.9Hz, 1H), 8.63 (dd, J=5.0, 1.6 Hz, 1H), 7.88 (td, J=7.7, 1.7 Hz, 1H),7.77 (d, J=2.0 Hz, 1H), 7.59 (s, 1H), 7.50-7.37 (m, 2H), 7.28-7.12 (m,5H), 7.01 (d, J=8.2 Hz, 1H), 6.87 (t, J=7.5 Hz, 1H), 5.20 (s, 2H), 4.46(s, 2H), 4.34 (s, 2H), 4.31 (s, 2H), 3.62 (s, 3H), 2.94 (s, 3H). (ESI+)m/z 541.1 (M+H)⁺.

Example 265(R)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 265a (R)-2-bromo-4-(ethylsulfonyl)-N-(1-phenylethyl)aniline

A mixture of Example 2b (661 mg, 2.476 mmol), (R)-1-phenylethanamine(526 mg, 4.340 mmol), and N-ethyl-N-isopropylpropan-2-amine (1.12 mL,6.420 mmol) in dimethylsulfoxide (12 mL) was heated at 100° C. for 16hours. The mixture was cooled to ambient temperature and partitionedbetween saturated aqueous ammonium chloride and ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 2% ethanol and 6% ethyl acetate in heptane) to provide the titlecompound.

Example 265b(R)-4-(5-(ethylsulfonyl)-2-((1-phenylethyl)amino)phenyl)-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 265a (320 mg, 0.869 mmol), Example if (558 mg, 1.30mmol), cesium fluoride (528 mg, 3.480 mmol) andtetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol) wassparged with argon for 15 minutes followed by the addition of a degasseddimethoxyethane (20 mL) and methanol (10 mL) mixture. The reactionmixture was heated at 85° C. for 2.5 hours. The mixture was cooled toambient temperature and partitioned between saturated aqueous sodiumchloride and ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and concentrated to provide the titlecompound.

Example 265c(R)-4-(5-(ethylsulfonyl)-2-((1-phenylethyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 265b (170 mg, 0.262 mmol) was dissolved in dioxane (20 mL). Tothis mixture was added 5N aqueous sodium hydroxide solution (5 mL) andthe mixture was stirred at 85° C. for 4 hours. The mixture waspartitioned between saturated aqueous ammonium chloride and ethylacetate. The organic layer was dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by flashchromatography (silica gel, 1-2% methanol in dichloromethane) to providethe title compound.

Example 265d(R)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

A mixture of Example 265c (140 mg, 0.321 mmol) and paraformaldehyde (39mg, 1.286 mmol) in tetrahydrofuran (10 mL) was stirred at ambienttemperature. To resulting suspension was added 1M solution of titaniumtetrachloride (2.57 mL). The reaction mixture was stirred for 4 hours atambient temperature and then added to a mixture of saturated aqueoussodium bicarbonate and ethyl acetate. The organic layer was separatedand the aqueous layer extracted with ethyl acetate. The combined organiclayers were dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by recrystallization frommethanol and dimethysulfoxide to provide the title compound (109 mg,76%)¹H NMR (400 MHz, 90° C., DMSO-d₆) δ 11.50 (s, 1H), 8.09 (d, J=2.3Hz, 1H), 7.64 (s, 1H), 7.60 (dd, J=8.3, 2.2 Hz, 1H), 7.41 (d, J=8.3 Hz,1H), 7.29-7.12 (m, 5H), 6.91 (s, 1H), 4.38 (q, J=6.7 Hz, 1H), 4.23-4.01(m, 2H), 3.67 (s, 3H), 3.28 (q, J=7.4 Hz, 2H), 1.22 (d, J=6.6 Hz, 3H),1.16 (t, J=7.3 Hz, 3H). (ESI+) m/z 448.0 (M+H)⁺.

Example 26610-methyl-4-(pyridin-2-yl)-7-(pyrrolidin-1-ylsulfonyl)-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-oneExample 266a 3-bromo-2-chloro-5-(pyrrolidin-1-ylsulfonyl)pyridine

5-bromo-6-chloropyridine-3-sulfonyl chloride (4.7 g, 16.2 mmol) indichloromethane (60 mL) at 0° C. was treated drop-wise with pyrrolidine(2.7 mL, 32.3 mmol) and stirred for 20 minutes at 0° C. The ice bath wasremoved and stirring was continued at ambient temperature for 45minutes. The reaction mixture was concentrated, slurried in water andfiltered. The solid was then slurried in diethyl ether and filtered togive 4.66 g (88%) of the title compound.

Example 266b

To a mixture of Example 266a (1 g, 3.1 mmol) and pyridin-2-amine (0.36g, 3.8 mmol) in dimethyl sulfoxide (10 mL) was added sodium hydride(0.25 g, 6.2 mmol). The mixture was stirred at ambient temperature for1.5 hours and then at 50° C. for 1 hour. The reaction mixture was cooledto ambient temperature and water was added to induce precipitation. Thesolid was collected by filtration, rinsed with additional water anddried by pulling air through. The solid was then slurried in diethylether, stirred for 1 hour, and filtered. The diethyl ether filtrate wasconcentrated. Both the solid as well as the residue from theconcentration were purified individually by flash chromatography (silicagel, 5 to 60% ethyl acetate in heptanes) and then combined to give 0.785g (67%) of the title compound.

Example 266c6-methyl-4-(2-(pyridin-2-ylamino)-5-(pyrrolidin-1-ylsulfonyl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 266b (0.066 g, 0.173 mmol), Example 1f (0.064 g, 0.15 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.004 g, 4.5 μmol),1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.004 g,0.015 mmol) and sodium carbonate (0.068 g, 0.645 mmol) were combined andsparged with nitrogen for 30 minutes. To this were addednitrogen-sparged 1,4-dioxane (0.8 mL) and water (0.2 mL). The reactionmixture was stirred at 60° C. for 4 hours and then partitioned betweenethyl acetate and water. The organic layer was washed with saturatedaqueous sodium chloride, treated with 3-mercaptopropyl-functionalizedsilica gel for 20 minutes, dried over anhydrous magnesium sulfate,filtered through a plug of Celite, and concentrated. The residue waspurified by flash chromatography (silica gel, 0 to 100% ethyl acetate inheptanes) to provide 0.049 g (54%) of the title compound.

Example 266d6-methyl-4-(2-(pyridin-2-ylamino)-5-(pyrrolidin-1-ylsulfonyl)pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 266c (0.047 g, 0.078 mmol) in 1,4-dioxane (0.75 mL)and ethanol (0.25 mL) was treated with sodium hydroxide solution (4 Maqueous, 0.1 mL, 0.4 mmol) and heated at 60° C. for 30 minutes. Thereaction mixture was cooled to ambient temperature and neutralized withhydrochloric acid solution (2 M aqueous). The resulting mixture waspartitioned between ethyl acetate and water, washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate,filtered, and concentrated. The residue was purified by reverse phaseHPLC (C18, acetonitrile/water (0.1% trifluoroacetic acid), 20-90%) toprovide 0.04 g (92%) of the title compound as the trifluoroacetic acidsalt.

Example 266e10-methyl-4-(pyridin-2-yl)-7-(pyrrolidin-1-ylsulfonyl)-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stirbar were addedExample 266d (0.031 g, 0.055 mmol), paraformaldehyde (0.008 g, 0.275mmol) and acetic acid (1 mL). The vial was capped and heated at 70° C.for 45 minutes. Additional paraformaldehyde (0.008 g, 0.275 mmol) wasadded and heating was continued at 80° C. for 90 minutes. Additionalparaformaldehyde (0.016 g, 0.55 mmol) was again added and heating wascontinued overnight at 80° C. The reaction mixture was concentrated andthen taken up in acetonitrile (3 mL). Saturated sodium bicarbonatesolution was added to achieve pH=10. Water (0.5 mL) was added to providea homogeneous solution. The mixture was heated at 50° C. overnight. Thereaction mixture was cooled to ambient temperature, diluted with water(5 mL) and neutralized with hydrochloric acid solution (2 M aqueous).The layers were separated. The aqueous layer was extracted with ethylacetate. The organic layers were combined and concentrated. The residuewas purified by reverse phase HPLC (C18, acetonitrile/water (0.1%trifluoroacetic acid), 15-90%) to provide 0.007 g (21%) of the titlecompound as the trifluoroacetic acid salt. ¹H NMR (500 MHz, DMSO-d₆) δ11.97 (d, J=1.83 Hz, 1H), 8.75 (d, J=2.14 Hz, 1H), 8.62 (d, J=2.14 Hz,1H), 8.09 (dd, J=5.04, 1.07 Hz, 1H), 7.92 (s, 1H), 7.46 (m, 1H), 7.34(d, J=2.75 Hz, 1H), 6.73 (dd, J=6.71, 5.49 Hz, 1H), 6.57 (d, J=8.54 Hz,1H), 5.15 (s, 2H), 3.64 (s, 3H), 3.31 (m, 4H), 1.74 (m, 4H). LCMS m/z463.21.

Example 267(S)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 267 was prepared according to the procedure used for thepreparation of Example 265, substituting (S)-1-phenylethanamine for(R)-1-phenylethanamine to provide the title compound. ¹H NMR (400 MHz,90° C., DMSO-d₆) δ 11.52 (s, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.65 (s, 1H),7.60 (dd, J=8.4, 2.2 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.29-7.12 (m, 5H),6.91 (d, J=2.6 Hz, 1H), 4.38 (q, J=6.6 Hz, 1H), 4.22-4.01 (m, 2H), 3.67(s, 3H), 3.29 (q, J=7.4 Hz, 2H), 3.19 (s, 2H), 1.22 (d, J=6.6 Hz, 3H),1.16 (t, J=7.3 Hz, 3H). (ESI+) m/z 448.0 (M+H)⁺.

Example 268 (R)-methyl3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate

The product from Example 82 was purified by chiral chromatography on aChiralpak OJ-H column (21×250 mm, 5 micron) eluting with a 7:13 mixtureof methanol/carbon dioxide. Fractions of the first eluted enantiomerwere collected and concentrated. The compound isolated was randomlyassigned as the (R) enantiomer. ¹H NMR (500 MHz, DMSO-d₆) δ 11.91 (s,1H), 7.85 (d, J=1.5 Hz, 1H), 7.70 (s, 1H), 7.24 (dd, J=8.2, 1.7 Hz, 1H),7.13 (s, 1H), 7.11-7.06 (m, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.97-6.85 (m,2H), 5.04 (t, J=7.6 Hz, 1H), 4.57-4.42 (m, 2H), 3.64 (s, 3H), 3.55 (s,3H), 2.93 (s, 3H), 2.46-2.36 (m, 2H), 1.96-1.85 (m, 1H), 1.59-1.48 (m,1H). (ESI+) m/z 542 (M+H)⁺.

Example 269 (S)-methyl3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate

The product from Example 82 was purified by chiral chromatography on aChiralpak OJ-H column (21×250 mm, 5 micron) eluting with a 7:13 mixtureof methanol/carbon dioxide. Fractions of the second eluted enantiomerwere collected and concentrated. The compound isolated was randomlyassigned as the (S) enantiomer. ¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s,1H), 7.85 (d, J=1.6 Hz, 1H), 7.69 (s, 1H), 7.24 (dd, J=8.2, 1.7 Hz, 1H),7.12 (s, 1H), 7.11-7.04 (m, 1H), 6.99 (d, J=8.2 Hz, 1H), 6.96-6.84 (m,2H), 5.03 (t, J=7.6 Hz, 1H), 4.57-4.40 (m, 2H), 3.64 (s, 3H), 3.55 (s,3H), 2.93 (s, 3H), 2.46-2.37 (m, 2H), 1.97-1.84 (m, 1H), 1.60-1.47 (m,1H). (ESI+) m/z 542 (M+H)⁺.

Example 2704-(2,4-difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 270a 4-bromo-2-iodo-7-methoxy-1-tosyl-1H-pyrrolo [2,3-c]pyridine

To a solution of n-butyl lithium (2.5 M, 36 mL, 90 mmol intetrahydrofuran) in anhydrous tetrahydrofuran (200 mL) was addeddiisopropylamine (7.33 g, 72.4 mmol) dropwise at −70° C. and then thereaction mixture was stirred at −70° C. to −50° C. for 45 minutes. Tothe solution of Example 1c (23.0 g, 60.3 mmol) in anhydroustetrahydrofuran (400 mL) was added the above lithium diisopropylamidesolution dropwise at −70° C. and then stirred for 1.5 hours. Then thesolution of iodine (35.2 g, 139 mmol) in anhydrous tetrahydrofuran (300mL) was added dropwise to the above mixture at −70° C. The reactionmixture was stirred at −70° C. for another 3 hours and poured intoaqueous Na₂S₂O₃ solution. The suspension was filtered and the filtercake was washed with dichloromethane and then dried to give the titlecompound (20 g, 39.4 mmol, 65.4% yield) as white solid.

Example 270b 4-bromo-2-iodo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To the reaction mixture of Example 270a (15 g, 29.6 mmol) and sodiumiodide (7.09 g, 47.3 mmol) in acetonitrile (300 mL) was addedchlorotrimethylsilane (5.88 mL, 46.0 mmol) dropwise at room temperature.The reaction mixture was stirred at room temperature for 1 hour. Water(0.266 mL, 14.79 mmol) was added dropwise to the reaction mixture andthe reaction mixture was stirred at 65° C. for 4 hours. After cooling toroom temperature, the reaction mixture was filtered to give crudeproduct, which was then re-dissolved in dichloromethane. The solid wasfiltered off and the filtrate was concentrated under reduced pressure togive title compound (11 g, 22.31 mmol, 75% yield) as white solid.

Example 270c4-bromo-2-iodo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of Example 270b in dimethylformamide (51.7 mL) was addedsodium hydride (0.538 g, 13.45 mmol) in portions at 0° C., and themixture was stirred for 30 minutes, followed by the dropwise addition ofiodomethane (0.839 mL, 13.45 mmol). The resulting mixture was stirred atroom temperature overnight. The reaction mixture was quenched withsaturated aqueous ammonium chloride solution. The resulting suspensionwas filtered and the filter cake was dissolved in dichloromethane, driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was washed with ethyl acetate and then dried toafford the title compound (5 g, 9.86 mmol, 95% yield).

Example 270d4-bromo-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 270c (0.431 g, 0.85 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.177 g, 0.850 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.019g, 0.021 mmol),1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (0.025 g,0.085 mmol), and sodium carbonate (0.135 g, 1.275 mmol) in dioxane (5mL) and water (1.25 mL) was stirred at 50° C. for 3 hours. The mixturewas concentrated to dryness and extracted with ethyl acetate (20 mL).The filtrate was concentrated and the residue purified by silica gelflash chromatography (petroleum ether/ethyl acetate 1:1-0:1) to give thetitle compound (0.353 g, 0.697 mmol, 82% yield).

Example 270e6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 270d (0.5 g, 1.084 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.330 g,1.301 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(0.079 g, 0.108 mmol), and potassium acetate (0.160 g, 1.626 mmol) in1,4-dioxane (5 mL) was stirred at 100° C. for 16 hours. The mixture wasfiltered and concentrated. The residue was purified by silica gel flashchromatography (petroleum ether/ethyl acetate 1:1-0:1) to give the titlecompound (0.3 g, 0.395 mmol, 36.5% yield).

Example 270f 2-bromo-N-(2,4-difluorophenyl)-4-(methylsulfonyl)aniline

A mixture of 2-bromo-4-(methylsulfonyl) aniline (0.8 g, 3.20 mmol),2,4-difluoro-1-iodobenzene (0.768 g, 3.20 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.146 g, 0.160 mmol), X-phos(2.78 g, 4.80 mmol), and cesium carbonate (0.104 g, 0.320 mmol) in1,4-dioxane (10 mL) was stirred at 100° C. for 16 hours. The mixture wasfiltered and the filtrate was concentrated to dryness. The residue waswashed with petroleum ether/ethyl acetate 1:1 to the title compound (0.9g, 2.485 mmol, 78% yield).

Example 270g4-(2-((2,4-difluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 270e (150 mg, 0.295 mmol), Example 270f (107 mg,0.295 mmol), tris(dibenzylideneacetone)dipalladium(0) (6.75 mg, 7.38tmol), potassium phosphate, dibasic (77 mg, 0.443 mmol), and1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (8.62 mg,0.030 mmol) in 1,4-dioxane (12 mL) and water (3.00 mL) was stirred at60° C. for 3 hours. The mixture was concentrated to dryness andextracted with ethyl acetate (20 mL). The filtrate was concentrated andthe residue was purified by flash chromatography (silica gel, petroleumether/ethyl acetate 1:1-0:1) to provide the title compound (150 mg,0.158 mmol, 53.6% yield).

Example 270h4-(2-((2,4-difluorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of Example 270g (50 mg, 0.075 mmol) in 1,4-dioxane (10 mL)was added sodium hydroxide (50 mg, 1.250 mmol) and water (2 mL). Themixture was stirred at 80° C. for 5 hours. The mixture was adjusted topH 5 by 1N HCl and then extracted with ethyl acetate. The organic phasewas dried over anhydrous saturated sodium sulfate, filtered, andconcentrated to give the crude product (50 mg, 0.041 mmol, 54.7% yield)as a yellow solid, which was used in the next step without furtherpurification.

Example 270i4-(2,4-difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To a solution of Example 270h (100 mg, 0.196 mmol) in tetrahydrofuran (5mL) was added paraformaldehyde (5.89 mg, 0.196 mmol) and TiCl₄ (0.022mL, 0.196 mmol) at 0° C., and the mixture was stirred at ambienttemperature for 3 hours. The mixture was diluted with water (10 mL) andethyl acetate (10 mL). It was then extracted with ethyl acetate threetimes. The combined organic layer was dried over anhydrous sodiumsulfate and then concentrated, and the residue was purified by reversephase preparative HPLC (C18, CH₃CN/water (0.1% trifluoroacetic acid),0-100% gradient) to afford the title compound (25 mg, 0.047 mmol, 23.94%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 1H), 8.26 (s, 1H), 8.15(s, 1H), 7.91 (d, J=14.6 Hz, 2H), 7.70 (d, J=8.4 Hz, 1H), 7.35-6.91 (m,4H), 4.85 (s, 2H), 3.90 (s, 3H), 3.68 (s, 3H), 3.31 (s, 3H). MS (ESI+)m/z 522.0 [M+H]⁺.

Example 2714-(4-chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 271a 2-bromo-N-(4-chlorophenyl)-4-(methylsulfonyl)aniline

A mixture of 2-bromo-4-(methylsulfonyl)aniline (0.8 g, 3.20 mmol),1-chloro-4-iodobenzene (0.763 g, 3.20 mmol),tris(dibenzylideneacetone)dipalladium (0.293 g, 0.320 mmol), cesiumcarbonate (0.052 g, 0.160 mmol) and Xantphos (2.78 g, 4.80 mmol) wasstirred at 90° C. for 16 hours under nitrogen. The reaction mixturecooled to ambient temperature and was filtered and the filtrated wasconcentrated. The residue was washed with petroleum ether/ethyl acetate(3:1) to provide the title compound (0.8 g, 1.996 mmol, 62.4% yield).

Example 271b4-(2-((4-chlorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

A mixture of Example 270e (150 mg, 0.295 mmol), Example 271a (106 mg,0.295 mmol), tris(dibenzylideneacetone)dipalladium (6.75 mg, 7.38 μmol),potassium phosphate, dibasic (77 mg, 0.443 mmol), and1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (8.62 mg,0.030 mmol) in dioxane (12 mL) and water (3 mL) was stirred at 50° C.for 3 hours. The mixture was concentrated and extracted with ethylacetate (20 mL). The filtrate was concentrated and the solid was washedwith petroleum ether/ethyl acete (1:1) to give the title compound (0.15g, 0.161 mmol, 54.5% yield).

Example 271c4-(2-((4-chlorophenyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

To a solution of Example 271b (150 mg, 0.227 mmol) in 1,4-dioxane (10mL) was added sodium hydroxide (80 mg, 2.000 mmol) and water (2 mL). Thereaction mixture was stirred at 60° C. for 3 hours. The mixture cooledto ambient temperature and the pH was adjusted to pH=5 by the additionof 1N HCl. The mixture was then extracted with ethyl acetate, dried overanhydrous sodium sulfate, filtered, and concentrated to give the titlecompound (80 mg, 0.079 mmol, 34.8% yield).

Example 271d4-(4-chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

To a 5-mL microwave vial equipped with a magnetic stir bar was addedExample 271c (70 mg, 0.134 mmol), paraformaldehyde (12.08 mg, 0.402mmol), and acetic acid (2 mL). The vial was capped and heated at 75° C.for 1 hour. The mixture was concentrated in vacuo. The residue wassuspended in methanol (10 mL) and acetic acid (1 mL) and heated at 85°C. for 20 minutes and then allowed to cool to ambient temperature. Theresulting solid was collected by filtration and washed with methanol togive the title compound as an off white solid. ¹H NMR (300 MHz, DMSO-d₆)δ 12.12 (s, 1H), 8.38 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.97-7.82 (m,2H), 7.58 (d, J=8.3 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.18 (d, J=8.6 Hz,2H), 5.12 (s, 1H), 4.61 (s, 1H), 3.94 (s, 3H), 3.60 (s, 3H), 3.34-3.09(m, 3H). MS (ESI+) m/z 518.0 [M+H]⁺.

Example 272(R)—N-ethyl-7-(ethylsulfonyl)-10-methyl-1-oxo-4-(1-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamideExample 272a4-bromo-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxylicacid

Example 208e (7.25 g, 24.2 mmol) in tetrahydrofuran/ethanol (1:2, 210mL) was heated at 75° C. to dissolve the solid. The mixture was thencooled to 35° C. To this solution was added 1M aqueous lithium hydroxide(97 mL). The mixture was heated at 75° C. for 2 hours and then cooled toambient temperature. The reaction mixture was then mixed with 1N HCl(100 mL) and water (300 mL) and allowed to stir at ambient temperatureovernight. The resulting precipitate was collected by filtration, rinsedwith water, and then dried to provide the title compound (6.41 gm. 98%).

Example 272b4-bromo-N-ethyl-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 272a (5.4 g, 19.9 mmol) in dimethyl sulfoxide (100mL) was treated with2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (8.33 g, 21.91 mmol) andN-ethyl-N-isopropylpropan-2-amine (10.5 mL, 60.1 mmol) and stirred for 5minutes. Ethylamine solution (2 M in tetrahydrofuran) (11 mL, 22.00mmol) was added and stirring was continued at ambient temperature for 7hours. The reaction mixture was then diluted with 600 mL of water andstirred overnight at ambient temperature. The resulting solid wascollected by filtration and rinsed with 1 L of water. The solid wasdried to provide the title compound (5.54 g, 93%).

Example 272cN-ethyl-6-methyl-7-oxo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 272b (5.4 g, 18.11 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (13.80 g,54.3 mmol), X-Phos (0.363 g, 0.761 mmol),tris(dibenzylideneacetone)dipalladium (0.166 g, 0.181 mmol), and ovendried potassium acetate (5.33 g, 54.3 mmol) was degassed with a streamof nitrogen blowing into the flask and over the solids to purge theflask for about 1 hour. To this mixture was then added via cannuladegassed, anhydrous dioxane (60 mL) and the mixture was heated at 75° C.overnight. The reaction mixture was cooled to ambient temperature andthen diluted with water and ethyl acetate and stirred for 30 minutes.The mixture was diluted futher with ethyl acetate and methanol was addedto help the solids dissolve. The mixture was partitioned. The resultingorganic layer was washed with saturated aqueous sodium chloride, and thecombined aqueous washes were back extracted with 10% methanol/ethylacetate. The combined organic extracts were stirred with 10 g.SiliaMetS® Thiol palladium scavenger (Silicycle) for one hour. Anhydroussodium sulfate was added directly to this mixture and stirring continuedfor another 30 minutes. The entire mixture was then filtered through aBuchner funnel, rinsed with ethyl acetate, and the resulting filtrateconcentrated under reduced pressure. The resulting residue was mixedwith 200 mL of 10% diethyl ether/heptane and sonicated for 30 minutes.The resulting solid was collected by vacuum filtration, washed with 100mL of 10% % diethyl ether/heptane followed by 200 mL of heptane, anddried to provide the title compound (5.1 g, 82% yield).

Example 272d (R)-2-bromo-4-(ethylsulfonyl)-N-(1-phenylpropyl)aniline

A mixture of Example 2b (522 mg, 1.954 mmol), (R)-1-phenylpropan-1-amine(801 mg, 5.860 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.683 mL,3.910 mmol) in dimethylsulfoxide (10 mL) was heated at 120° C. for 18hours. The mixture was cooled to ambient temperature and partitionedbetween saturated aqueous ammonium chloride and ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The residue was purified by flash chromatography (silicagel, 2% ethanol and 6% ethyl acetate in heptane) to provide the titlecompound.

Example 272e(R)—N-ethyl-4-(5-(ethylsulfonyl)-2-((1-phenylpropyl)amino)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamide

A mixture of Example 272d (288 mg, 0.753 mmol), Example 272c (200 mg,0.579 mmol), potassium phosphate (369 mg, 1.738 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (20.3 mg,0.070 mmol) and tris(dibenzylideneacetone)dipalladium(0) (21.2 mg, 0.023mmol) was sparged with argon for 15 minutes followed by addition ofdegassed tetrahydofuran (6 mL) and water (1.5 mL) mixture. The reactionmixture was heated at 60° C. for 3 hours. The mixture was cooled toambient temperature and partitioned between saturated aqueous sodiumchloride and ethyl acetate. The organic layer was dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purifiedby flash chromatography (silica gel, 8% ethanol and 25% ethyl acetate inheptane) to provide the title compound.

Example 272f(R)—N-ethyl-7-(ethylsulfonyl)-10-methyl-1-oxo-4-(1-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide

A mixture of Example 272e (100 mg, 0.192 mmol) and paraformaldehyde (23mg, 0.768 mmol) in tetrahydrofuran (6 mL) was stirred at ambienttemperature. To resulting suspension was added 1M solution of titaniumtetrachloride (0.39 mL). The reaction mixture was stirred for 1 hour atambient temperature and then at 60° C. for 2 hours. The mixture wascooled to ambient temperature and partitioned between saturated aqueoussodium chloride and ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate, filtered, and concentrated. The residue waspurified by recrystallization from methanol to provide the titlecompound (87 mg, 85%)¹H NMR (400 MHz, 90° C., DMSO-d₆) δ 11.79 (s, 1H),8.07 (d, J=2.2 Hz, 1H), 7.94 (t, J=5.4 Hz, 1H), 7.64-7.54 (m, 2H), 7.34(d, J=8.4 Hz, 1H), 7.27-7.12 (m, 5H), 4.76 (d, J=16.5 Hz, 1H), 4.48 (d,J=16.5 Hz, 1H), 4.27 (t, J=7.1 Hz, 1H), 3.68 (s, 3H), 3.21-3.32 (m, 4H),1.76 (p, J=7.2 Hz, 2H), 1.15 (dt, J=16.7, 7.3 Hz, 6H), 0.52 (t, J=7.2Hz, 3H). (ESI+) m/z 532.9 (M+H)⁺.

Example 27310-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 273a N-(2-bromo-4-((methylsulfonyl)methyl)phenyl)pyridin-2-amine

Example 273a was prepared according to the procedure used for thepreparation of Example 58h, substituting 2-iodopyridine for1-chloro-4-iodobenzene, to give the title compound.

Example 273b6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 273b was prepared according to the procedure used for thepreparation of Example 270g, substituting Example 273a for Example 270f,to give the title compound.

Example 273c6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-((methylsulfonyl)methyl)-2-(pyridin-2-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 273c was prepared according to the procedure used for thepreparation of Example 270h, substituting Example 273b for Example 270g,to give the title compound.

Example 273d10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 273d was prepared according to the procedure used for thepreparation of Example 270i, substituting Example 273c for Example 270h,to give the title compound. ¹H NMR (400 MHz, DMSO-d₆): δ 11.99 (s, 1H),8.23 (s, 1H), 8.02 (s, 1H), 7.92 (m, 2H), 7.63 (s, 1H), 7.46 (dd, J=8.0,1.6 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.28-7.24 (m, 1H), 6.47 (dd, J=6.7,5.2 Hz, 1H), 6.01 (d, J=8.4 Hz, 1H), 5.94 (d, J=15.6 Hz, 1H), 4.63 (d,J=13.6 Hz, 1H), 4.52 (d, J=13.6 Hz, 1H), 4.33 (d, J=15.7 Hz, 1H), 3.94(s, 3H), 3.59 (s, 3H), 3.01 (s, 3H). MS (ESI+) m/z 501.0 [M+H]⁺.

Example 27410-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 274a 2-bromo-4-(methylsulfonyl)-N-phenylaniline

Example 274a was prepared according to the procedure used for thepreparation of Example 270f, substituting iodobenzene for2,4-difluoro-1-iodobenzene, to give the title compound.

Example 274b6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(phenylamino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 274b was prepared according to the procedure used for thepreparation of Example 270g, substituting Example 274a for Example 270f,to give the title compound.

Example 274c6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(phenylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 274c was prepared according to the procedure used for thepreparation of Example 270h, substituting Example 274b for Example 270g,to give the title compound.

Example 274d10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 274d was prepared according to the procedure used for thepreparation of Example 270i, substituting Example 274c for Example 270h,to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H),8.37 (d, J=2.1 Hz, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.92 (dd, J=8.2, 2.2Hz, 1H), 7.85 (s, 1H), 7.56 (d, J=8.2 Hz, 1H), 6.98-6.90 (m, 2H), 6.51(s, 1H), 6.23 (d, J=8.0 Hz, 2H), 3.95 (s, 3H), 3.59 (s, 3H), 3.38 (s,3H). MS (ESI+) m/z 486.0 [M+H]⁺.

Example 27510-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 275a N-(2-bromo-4-(methylsulfonyl)phenyl)pyridin-2-amine

Example 274a was prepared according to the procedure used for thepreparation of Example 270f, substituting 2-iodopyridine for2,4-difluoro-1-iodobenzene, to give the title compound.

Example 275b6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(pyridin-2-ylamino)phenyl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 275b was prepared according to the procedure used for thepreparation of Example 270g, substituting Example 275a for Example 270f,to give the title compound.

Example 275c6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-(5-(methylsulfonyl)-2-(pyridin-2-ylamino)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 275c was prepared according to the procedure used for thepreparation of Example 270h, substituting Example 275b for Example 270g,to give the title compound.

Example 275d10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 275d was prepared according to the procedure used for thepreparation of Example 270i, substituting Example 275c for Example 270h,to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 12.06 (s, 1H),8.37 (d, J=2.0 Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.97-7.85 (m, 3H),7.61 (d, J=8.3 Hz, 1H), 7.35 (s, 1H), 6.56 (d, J=6.1 Hz, 1H), 6.13 (d,J=8.5 Hz, 1H), 5.88 (d, J=16.1 Hz, 1H), 4.37 (s, 1H), 3.95 (s, 3H), 3.61(s, 3H), 3.37 (s, 3H).MS (ESI+) m/z 487.0 [M+H]+.

Example 2764-(4-fluorophenyl)-10-methyl-2-(1-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-oneExample 276a2-bromo-N-(4-fluorophenyl)-4-((methylsulfonyl)methyl)aniline

Example 276a was prepared according to the procedure used for thepreparation of Example 58h, substituting 1-fluoro-4-iodobenzene for1-chloro-4-iodobenzene, to give the title compound.

Example 276b4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 276b was prepared according to the procedure used for thepreparation of Example 270g, substituting Example 276a for Example 270f,to give the title compound.

Example 276c4-(2-((4-fluorophenyl)amino)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one

Example 276c was prepared according to the procedure used for thepreparation of Example 270h, substituting Example 276b for Example 270g,to give the title compound.

Example 276d4-(4-fluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one

Example 276d was prepared according to the procedure used for thepreparation of Example 270i, substituting Example 276c for Example 270h,to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H),8.29 (s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.47 (d, J=8.0Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 6.75 (t, J=8.9 Hz, 2H), 6.13 (dd,J=9.2, 4.4 Hz, 2H), 4.57 (s, 2H), 3.94 (s, 3H), 3.57 (s, 3H), 3.00 (s,3H). MS (ESI+) m/z 518.0 [M+H]⁺.

Biological Examples Bromodomain Domain Binding Assay

A time-resolved fluorescence resonance energy transfer (TR-FRET) assaywas used to determine the affinities of compounds of the Examples listedin Table 1 for each bromodomain of BRD4. His-tagged first (BD1: aminoacids K57-E168) and second (BD2: amino acids E352-E168) bromodomains ofBRD4 were expressed and purified. An Alexa647-labeled BET-inhibitor wasused as the fluorescent probe in the assay.

Synthesis of Alexa647-Labeled Bromodomain Inhibitor Compound2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid

Methyl2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate(WO 2006129623)(100.95 mg, 0.243 mmol was suspended in 1 mL methanol towhich was added a freshly prepared solution of lithium hydroxidemonohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken at ambienttemperature for 3 hours. The methanol was evaporated and the pH adjustedwith aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) and extractedfour times with ethyl acetate. The combined ethyl acetate layers weredried over magnesium sulfate and evaporated to afford2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (85.3 mg, 87.0%); ESI-MS m/z=401.1 [(M+H)⁺] which was used directlyin the next reaction.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate)

2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (85.3 mg, 0.213 mmol) was combined with2,2′-(ethane-1,2-diylbis(oxy))diethanamine (Sigma-Aldrich, 0.315 mg,2.13 mmol) were combined in 5 mL anhydrous dimethylformamide.(1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphoniumhexafluorophosphate(V) (PyBOB, CSBio, Menlo Park Calif.; 332 mg, 0.638mmol) was added and the reaction shaken at ambient temperature for 16hours. The reaction was diluted to 6 mL with dimethylsulfoxide:water(9:1, v:v) and purified in two injections with time collection WatersDeltapak C18 200×25 mm column eluted with a gradient of 0.1%trifluoroacetic acid (v/v) in water and acetonitrile. The fractionscontaining the two purified products were lyophilized to affordN-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate) (134.4 mg, 82.3%); ESI-MS m/z=531.1[(M+H)+]; 529.1 [(M−H)⁺] and(S,Z)—N,N′-(2,2′-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)bis(2,2,2-trifluoroacetate) (3.0 mg, 1.5%); ESI-MS m/z=913.2 [(M+H)+];911.0 [(M−H)⁻].

N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(2,2,2-trifluoroacetate)

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate) (5.4 mg, 0.0071 mmol) was combined withAlexa Fluor® 647 carboxylic Acid, succinimidyl ester (Life Technologies,Grand Island, N.Y.; 3 mg, 0.0024 mmol) were combined in 1 mL anhydrousdimethylsulfoxide containing diisopropylethylamine (1% v/v) and shakenat ambient temperature for 16 hours. The reaction was diluted to 3 mLwith dimethylsulfoxide:water (9:1, v:v) and purified in one injectionwith time collection Waters Deltapak C18 200×25 mm column eluted with agradient of 0.1% trifluoroacetic acid (v/v) in water and acetonitrile.The fractions containing the purified product were lyophilized to affordN-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(2,2,2-trifluoroacetate)(1.8 mg); MALDI-MS m/z=1371.1, 1373.1 [(M+H)⁺] as a dark blue powder.

Assay

Compound dilution series were prepared in DMSO via an approximately3-fold serial dilution from one of the following:

Assay method C: 1250 μM-21 nMAssay method D: 500 μM-8.5 nMAssay method E: 0.47 mM to 7.8 nMAssay method F: 250 μM-4.2 nMAssay method G: 0.047 mM to 0.78 nMor 5-fold serial dilution from one of the following:Assay method A: 2.5 mM-800 nMAssay method B: 2.5 mM-797 nM

For Assay methods A, C, D, and F: Compounds were then diluted 6:100 inassay buffer (20 mM Sodium Phosphate, pH 6.0, 50 mM NaCl, 1 mMEthylenediaminetetraacetic acid, 0.01% Triton X-100, 1 mMDL-Dithiothreitol) to yield 3× working solutions. Six microliters (μL)of the working solution was then transferred to white, low-volume assayplates (Costar #3673). A 1.5× assay mixture containing His-taggedbromodomain, Europium-conjugated anti-His antibody (Invitrogen PV5596)and the Alexa-647-conjugated probe molecule was also prepared. Twelve μLof this solution were added to the assay plate to reach a final volumeof 18 μL.

For Assay methods B, E, and G: Compound dilutions were added directlyinto white, low-volume assay plates (Perkin Elmer Proxiplate 384 Plus#6008280) using a Labcyte Echo in conjunction with Labcyte Access andThermo Multidrop CombinL robotics. Compounds were then suspended ineight microliters (μL) of assay buffer (20 mM Sodium Phosphate, pH 6.0,50 mM NaCl, 1 mM Ethylenediaminetetraacetic acid disodium saltdihydrate, 0.01% Triton X-100, 1 mM DL-Dithiothreitol) containingHis-tagged bromodomain, Europium-conjugated anti-His antibody(Invitrogen PV5596) and Alexa-647-conjugated probe.

The final concentration of 1× assay mixture for assay methods A, B, C,D, E, F, and G contains 2% DMSO, 8 nM His-tagged bromodomain, 1 nMEuropium-conjugated anti-His-tag antibody and 100 nM or 30 nM probe (forBDI or BDII, respectively) and compound concentration in the range of:50 μM-16 nM for method A, 49.02 μM-15.63 nM for method B, 25 μM-423 μMfor method C, 10 μM-169 μM for method D, 9.19 μM-150 μM for method E, 5μM-85 μM for method F, and 0.92 μM-15 μM for method G.

After a one-hour equilibration at room temperature, TR-FRET ratios weredetermined using an Envision multilabel plate reader (Ex 340, Em495/520).

TR-FRET data were normalized to the means of 24 no-compound controls(“high”) and 8 controls containing 1 t.M un-labeled probe (“low”).Percent inhibition was plotted as a function of compound concentrationand the data were fit with the 4 parameter logistic equation to obtainICsos. Inhibition constants (K_(i)) were calculated from the ICsos,probe K_(d) and probe concentration. Typical Z′ values were between 0.65and 0.75. The minimum significant ratio was determined to evaluate assayreproducibility (Eastwood et al., (2006) J Biomol Screen, 11: 253-261).The MSR was determined to be 2.03 for BDI and 1.93 for BDII, and amoving MSR (last six run MSR overtime) for both BDI and BDII wastypically <3. The K_(i) values are reported in Table 1.

MX-1 Cell Line Proliferation Assay

The impact of compounds of the Examples on cancer cell proliferation wasdetermined using the breast cancer cell line MX-1 (ATCC) in a 3-dayproliferation assay and the data are reported in Table 1. MX-1 cellswere maintained in RPMI 1640 medium (Sigma) supplemented with 10% FBS at37° C. and an atmosphere of 5% CO₂. For compound testing, MX-1 cellswere plated in 96-well black bottom plates at a density of 5000cells/well in 90 μL of culture media and incubated at 370 overnight toallow cell adhesion and spreading. Compound dilution series wereprepared in DMSO via a 3-fold serial dilution from 3 mM to 0.1 μM. TheDMSO dilution series were then diluted 1:100 in phosphate bufferedsaline, and 10 jμL of the resulted solution were added to theappropriate wells of the MX-1 cell plate. The final compoundconcentrations in the wells were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003,0.001, 0.0003, and 0.0001 μM or 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001,0.0003, 0.0001, and 0.00003 μM. After the addition of compounds, thecells were incubated for 72 more hours and the amounts of viable cellswere determined using the Cell Titer Glo assay kit (Promega) accordingto manufacturer suggested protocol.

Luminescence readings from the Cell Titer Glo assay were normalized tothe DMSO treated cells and analyzed using the GraphPad Prism softwarewith sigmoidal curve fitting to obtain EC_(50S). The minimum significantratio (MSR) was determined to evaluate assay reproducibility (Eastwoodet al., (2006) J Biomol Screen, 11: 253-261). The overall MSR wasdetermined to be 2.1 and a moving MSR (last six run MSR overtime) hasbeen <2.

TABLE 1 TR-FRET TR-FRET Binding Ki: Binding Ki: Cellular TR-FRET BRD4BRD4 proliferation: Compound assay (BDI_K57- (BDII_E352- EC₅₀ of Example# protocol E168) (μM) M457) (μM) (μM) 1 E 0.0327 0.0105 0.0272 2 E0.0246 0.00836 0.0192 3 E 0.046 0.00891 0.0487 4 E 2 3.09 ND 5 E 0.7650.758 ND 6 E 0.00108 0.00171 0.00201 7 B 0.0511 0.0267 0.0145 8 E0.000646 0.00377 0.00568 9 G 0.000453 0.00111 0.000721 10 E 0.006940.00599 0.0608 11 G 0.00161 0.00257 0.00164 12 G 0.00134 0.000472 0.004013 G 0.00484 0.00768 0.00726 14 E 0.0069 0.000882 0.0146 15 E 0.005220.000631 0.00875 16 E 0.0926 0.0189 0.337 17 E 0.165 0.0539 ND 18 E0.145 0.0241 0.343 19 E 0.246 0.0438 0.37 20 E 0.158 0.0245 0.544 21 G0.00443 0.003 0.00105 22 G 0.000875 0.00095 0.00171 23 E 0.0017 0.0007830.0070 24 E 0.000963 0.000801 0.00107 25 E 0.00174 0.000847 0.0087 26 G0.000701 0.000719 0.00103 27 E 0.00119 0.00101 0.00127 28 E 0.00110.00117 0.0137 29 E 0.00695 0.00274 0.00103 30 E 0.00498 0.00136 0.0013931 G 0.00167 0.00118 0.000752 32 G 0.00101 0.00114 0.00138 33 G 0.03830.0228 0.495 34 G 0.00245 0.00389 0.0147 35 G 0.0355 0.0951 0.331 36 G0.00505 0.00625 >1 37 G 0.00336 0.0024 >1 38 G >0.238 >0.408 ND 39G >0.238 >0.408 ND 40 G 0.0294 0.136 0.398 41 G 0.0495 0.0578 >1 42 G0.00156 0.00203 0.00544 43 G 0.00729 0.0247 ND 44 G 0.00261 0.002470.0487 45 G 0.00392 0.00375 0.141 46 G 0.0137 0.00748 0.152 47 G 0.001370.00127 0.00833 48 G 0.00112 0.000855 0.00441 49 G 0.00199 0.002210.00863 50 G 0.00344 0.00551 0.0422 51 G 0.00443 0.0132 0.174 52 G0.0174 0.00499 0.247 53 G 0.00478 0.0219 ND 54 G 0.00585 0.00145 ND 55 G0.00896 0.0159 0.146 56 G 0.0144 0.0353 0.197 57 G 0.0647 0.0906 ND 58 G0.00202 0.000617 0.00538 59 G 0.0031 0.000972 0.0038 60 G 0.00255 0.03310.115 61 G 0.0211 0.00374 >1 62 G 0.00723 0.00473 0.91 63 G 0.08220.0736 ND 64 G 0.00269 0.00285 0.0846 65 G >0.238 0.238 ND 66G >0.238 >0.408 ND 67 G >0.238 >0.408 ND 68 G 0.0127 0.00422 0.0401 69 G0.00325 0.00324 0.0431 70 G 0.00741 0.00188 0.131 71 G 0.0304 0.0267 ND72 G 0.0262 0.037 ND 73 G 0.0165 0.0194 ND 74 G >0.238 0.369 ND 75G >0.238 >0.408 ND 76 G >0.238 >0.408 ND 77 G >0.238 0.275 ND 78 G 0.2160.126 ND 79 G >0.238 >0.408 ND 80 G >0.238 >0.408 ND 81 G 0.0517 0.0323ND 82 G 0.0133 0.00112 0.979 83 G >0.238 >0.408 ND 84 G 0.00224 0.003860.0177 85 G 0.0108 0.0111 0.0489 86 G 0.0103 0.0139 ND 87 G 0.002540.0021 0.00469 88 G 0.00346 0.00176 ND 89 G 0.00577 0.00453 ND 90 G0.00132 0.00201 0.0306 91 G 0.00327 0.00115 0.00181 92 G 0.00374 0.00558ND 93 G 0.00284 0.00163 0.00259 94 G 0.00603 0.00349 0.00602 95 G0.00218 0.00253 0.0141 96 G 0.00346 0.00161 ND 97 G 0.00321 0.00135 ND98 G 0.00234 0.00315 0.00441 99 G 0.0155 0.00166 0.165 100 G 0.02980.00741 ND 101 G 0.00483 0.00277 ND 102 G 0.00941 0.0269 0.151 103 G0.00812 0.00471 ND 104 G 0.0347 0.0262 ND 105 G 0.00549 0.00268 0.0162106 G 0.00589 0.00191 0.0192 107 G 0.00642 0.00379 0.00704 108 G 0.01390.00211 0.165 109 G 0.0641 0.0156 ND 110 G 0.0417 0.0199 ND 111 G 0.00770.00331 0.084 112 G 0.0532 0.0152 ND 113 G 0.0856 0.0109 ND 114 G 0.1120.0255 ND 115 G 0.0087 0.00271 0.00783 116 G 0.016 0.0112 ND 117 G0.0723 0.00127 >1 118 G 0.0126 0.00138 0.174 119 G 0.0119 0.000602 0.134120 G 0.00928 0.00159 >1 121 G 0.00665 0.000799 >1 122 G 0.01080.000922 >1 123 G 0.00995 0.000983 >1 124 G 0.00884 0.00278 0.944 125 G0.00926 0.00236 0.342 126 G 0.0536 0.08 ND 127 G 0.00268 0.00135 0.0417128 G 0.0291 0.002 0.0729 129 G 0.0162 0.0025 0.25 130 G 0.215 0.0146 ND131 G 0.0107 0.00235 >1 132 G 0.0113 0.00314 >1 133 G 0.00929 0.00140.204 134 G 0.0144 0.00111 0.182 135 G 0.0114 0.00214 0.51 136 G 0.01320.00133 0.0492 137 G 0.0517 0.00387 0.24 138 G 0.0225 0.00194 0.256 139G 0.0175 0.00233 0.627 140 G 0.00999 0.00224 0.936 141 G 0.0208 0.01090.319 142 G 0.00861 0.00060 0.0518 143 G 0.0549 0.00306 0.175 144G >0.238 0.0188 0.318 145 G 0.0551 0.00138 0.0806 146 G 0.00142 0.0170.124 147 G 0.00702 0.00097 0.0203 148 G 0.00677 0.00054 0.0319 149 G0.00178 0.00082 0.00193 150 G 0.00405 0.0108 ND 151 G 0.00114 0.00230.00426 152 G 0.00718 0.011 ND 153 G 0.00372 0.00918 ND 154 G 0.05070.0531 ND 155 G 0.0427 0.0478 0.349 156 G 0.0468 0.0421 0.214 157 G0.0396 0.0239 0.0774 158 G 0.0603 0.0773 ND 159 G 0.0386 0.0198 0.0578160 G 0.125 0.118 ND 161 G 0.0321 0.0214 0.0416 162 G 0.0471 0.0604 ND163 G 0.0574 0.0454 ND 164 G 0.0417 0.030 0.0725 165 G 0.0814 0.0796 ND166 G 0.060 0.0733 ND 167 G 0.0692 0.0763 ND 168 G 0.0932 0.124 ND 169 G0.0124 0.00467 0.0699 170 G 0.00707 0.0252 0.0576 171 G 0.0164 0.0292 ND172 G 0.0578 0.0128 0.551 173 G 0.00672 0.00314 0.0199 174 G 0.01260.00153 0.239 175 G 0.015 0.0019 0.0999 176 G 0.00101 0.00355 0.0142 177G 0.00202 0.00127 0.00372 178 G 0.00436 0.00438 0.123 179 G 0.02010.0807 ND 180 G 0.00151 0.0027 ND 181 G 0.00333 0.0171 ND 182 G 0.001310.0020 0.00108 183 G 0.00384 0.0155 ND 184 G 0.00434 0.00682 ND 185 G0.00419 0.0102 0.0283 186 G 0.00421 0.0092 ND 187 G 0.00574 0.050 ND 188G 0.00364 0.00462 ND 189 G 0.00582 0.0223 ND 190 G 0.0267 0.0309 ND 191G 0.00100 0.00338 0.0107 192 G 0.00165 0.00108 0.00125 193 G 0.001850.0124 0.0317 194 G 0.00133 0.00038 0.00147 195 G 0.00266 0.000620.00377 196 G 0.00114 0.00172 0.00382 197 G 0.00152 0.00265 0.00266 198G 0.00159 0.00063 0.00069 199 G 0.00081 0.00121 0.0108 200 G 0.008180.00205 0.0342 201 G 0.00085 0.0032 0.0278 202 G 0.00079 0.00035 0.0043203 G 0.00099 0.00071 0.00543 204 G 0.0461 0.00122 >1 205 G 0.200.0291 >1 206 G 0.00096 0.00051 0.00141 207 G 0.00092 0.00209 0.00133208 G 0.00341 0.00115 0.0107 209 G 0.0012 0.00086 0.00654 210 G 0.001720.00080 0.0133 211 G 0.00567 0.00747 0.118 212 G 0.00239 0.0050 0.155213 G 0.00065 0.00042 0.0014 214 G 0.0408 0.00325 0.431 215 G 0.06570.00587 0.454 216 G 0.0573 0.0658 0.603 217 G 0.193 0.0426 >1 218 G0.00064 0.00064 0.00136 219 G 0.0399 0.00476 0.301 220 G 0.0516 0.002610.285 221 G 0.0316 0.0123 0.033 222 G 0.17 0.0294 0.16 223G >0.238 >0.408 ND 224 G 0.00164 0.0014 0.00584 225 G 0.00325 0.002390.0122 226 G 0.00384 0.00186 0.00782 227 G 0.00794 0.00118 0.134 228 G0.0245 0.00222 0.0849 229 G 0.00411 0.00196 0.0412 230 G >0.238 0.05810.528 231 G 0.039 0.00542 0.149 232 G 0.108 0.00848 0.363 233 G 0.006150.00377 ND 234 G 0.0103 0.0094 >1 235 G 0.0161 0.00651 0.162 236 G0.0859 0.030 >1 237 G 0.0218 0.0121 0.313 238 G 0.0621 0.0046 0.275 239G 0.0319 0.00212 0.294 240 G 0.00314 0.00193 0.0859 241 G 0.003070.00176 0.0515 242 G 0.0126 0.00378 >1 243 G 0.00185 0.00347 0.153 244 G0.00043 0.00102 0.00213 245 G 0.00054 0.00094 0.00109 246 G 0.004320.0036 0.0117 247 G 0.00222 0.00242 0.00494 248 G 0.00339 0.00329 0.0256249 G 0.0061 0.0191 0.0177 250 G 0.0088 0.0225 0.845 251 G >0.238 0.142ND 252 G 0.0161 0.00224 0.108 253 G 0.00070 0.00118 0.0013 254 G 0.001120.00071 0.0039 255 G 0.00453 0.00733 0.0343 256 G 0.00059 0.000540.00035 257 G 0.00234 0.00919 0.0211 258 G 0.00092 0.00239 0.00443 259 G0.0034 0.00305 0.019 260 G 0.00726 0.0034 0.219 261 G 0.009320.00778 >1.0 262 G 0.00937 0.0132 ND 263 G 0.00704 0.00807 >1.0 264 G0.00697 0.00153 0.899 265 G 0.0256 0.00421 0.17 266 G 0.0178 0.008150.0427 267 G 0.0727 0.0947 ND 268 G 0.0828 0.0164 ND 269 G 0.005690.00092 ND 270 G 0.011 0.00335 0.0807 271 G 0.00391 0.00164 0.0852 272 G0.0589 0.00635 ND 273 G 0.00112 0.00088 ND 274 G 0.00283 0.00156 ND 275G 0.00209 0.00085 ND 276 G 0.00119 0.00118 ND ND = not determined.

LPS (Lipopolysaccharide) Induced IL-6 Production Mouse Assay

Compounds of the Examples listed in Table 2 were assayed for theirability to inhibit LPS (lipopolysaccharide) induced IL-6 (Interleukin-6)production in mice. Fox Chase SCID® female mice (Charles Rivers Labs, 5per group) or CD1 female mice (5 per group) received an intraperitonealchallenge of lipopolysaccharide (2.5 mg/kg, L2630 E. coli 0111:B4) onehour after oral administration of compounds. Mice were euthanized 2hours after lipopolysaccharide injection, blood was removed by cardiacpuncture, and then the serum harvested from the blood samples was frozenat −80° C. On the day of the assay the serum samples were brought toroom temperature and then diluted 1:20 in phosphate-buffered salinecontaining 2% bovine serum albumin. Interleukin-6 measurements wereperformed using a cytokine assay from Meso Scale Discovery(Gaithersburg, Md.) for mouse serum analysis according to themanufacturer's protocol and read on a SECTOR Imager 6000 (Meso ScaleDiscovery, Gaithersburg, Md.) instrument. Statistical analysis wasperformed using Prism software (version 5.0) incorporating Dunnett's oneway ANOVA. The IL-6 mean and standard deviation of the group of vehicletreated animals were compared with the IL-6 mean and standard deviationof the group treated with drug. A p value <0.05 means that there is lessthan a 5% probability that the mean values in the two groups are equal.The % inhibition values in Table 2 all exhibited a p value less than0.05.

TABLE 2 Inhibition of LPS induced IL-6 production Compound of Example #% inhibition Mouse strain 6 64 SCID 7 53 SCID 8 53 SCID 9 79 SCID 12 90SCID 15 68 SCID 23 54 SCID 24 78 SCID 26 88 SCID 27 79 SCID 29 76 SCID30 81 SCID 31 83 SCID 42 86 CD1 58 39 CD1 59 68 CD1 60 44 CD1 149 86 CD1151 57 CD1 173 87 CD1 182 77 CD1 191 60 CD1 192 73 CD1 194 53 CD1 195 85CD1 196 79 CD1 198 86 CD1 199 90 CD1 202 47 CD1 206 76 CD1 207 65 CD1

Xenograft Tumor Growth Inhibition Assay

The effect of compounds of the examples to inhibit the growth of OPM-2xenograft tumors implanted in mice was evaluated. A suspension of cancercells (5×10⁶ per 0.1 mL) prepared in RPMI culture medium (Invitrogen,Carlsbad, Calif.) was diluted 1:1 with a solution of Matrigel™ (BDBiosciences, Franklin Lakes, N.J.) and inoculated subcutaneously intothe right hind flank of female SCID-beige (Charles River Labs) mice.Randomization into treatment and vehicle control groups (8-10/group)occurred when the mean tumor volume reached approximately 250 mm³.Compounds were formulated in 2.5% DMSO, 10% ethanol, 27.5% PEG 400, 60%Phosol 53 MCT. Administration of compound or vehicle was initiated onthe day following randomization and continued for 21 days. Tumors weremeasured twice a week throughout the treatment period using a pair ofcalipers and tumor volumes were calculated according to the formulaV=LxW²/2 (V: volume, mm³; L: length, mm. W: width, mm). Tumor growthinhibition was calculated based on the mean tumor volume measured on thefirst day that the mean volume of the vehicle group exceeded 2000 mm³according to the formula:

% TGI=100−(100×(mean tumor volume of treatment group/mean tumor volumeof control group))

Results are shown in Table 3.

TABLE 3 OPM-2 human multiple myeloma cancer xenograft model Compound ofDose route, % removed Example # mg/kg regimen % TGI^(a) from study^(b) 91.85 PO, QD x21 87*** 56 9 3.75 PO, QD x21 nd^(c) 100 12 1.5 IP, QD x2182**  11 12 1.5 IP, QD x21 91*** 22 12 3 IP, QD x21 89**  11 12 3 IP, QDx21 nd^(c) 100 12 3 PO, 3 on 4 81*** 0 off x3 weeks 12 3 PO, QD x1172*** 0 12 1.5 PO, QD x21 87*** 22 12 3 PO, QD x21 94*** 56 173 1.25 PO,QD x21 49**  0 173 2.5 PO, QD x21 nd^(c) 67 196 2.5 PO, QD x21 84*** 0196 5 PO, QD x21 92*** 44 199 1.25 PO, QD x21 91*** 38 199 2.5 PO, QDx21 nd^(c) 50 199 5 PO, QD x21 nd^(c) 50 207 0.25 PO, QD x21 60*** 0 2070.5 PO, QD x21 93*** 11 207 0.5 PO, QD x21 94*** 13 207 1.0 PO, QD x2197*** 44 213 0.5 PO, QD x21 82*** 13 213 1 PO, QD x21 96*** 25 213 1 PO,QD x21 95*** 13 213 2 PO, QD x21 nd^(c) 63 ^(a)The p values (asindicated by asterisks) are derived from Student's T test comparison oftreatment group vs. control group. ***p < 0.001, **p < 0.01, * p < 0.05.^(b)Percentage of treatment group that were removed from study due tomorbidity or weight loss in excess of 20%. ^(c)Not determined.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof. All publications, patents, and patent applications citedherein are hereby incorporated by reference in their entirety for allpurposes.

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof,

wherein Y¹ is N or CH; R¹ is CD3, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; R² isH or C₁-C₃ alkyl; Y³ is N or CR³; R³ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, —C(O)R^(3a), —C(O)OR^(3a),—C(O)NR^(3b)R^(3c), —S(O)R^(3d), —S(O)₂R^(3a), —S(O)₂NR^(3b)R^(3c), G¹;wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are eachindependently unsubstituted or substituted with 1 or 2 substituentsindependently selected from the group consisting of G¹, —CN,—C(O)R^(3a), —C(O)OR^(3a), —C(O)NR^(3b)R^(3c),—C(O)N(R^(3b))NR^(3b)R^(3c), —S(O)R^(3d), —S(O)₂R^(3a),—S(O)₂NR^(3b)R^(3c), —OR^(3a), —OC(O)R^(3d), —NR^(3b)R^(3c),N(R^(3b))C(O)R^(3d), N(R^(3b))SO₂R^(3d), N(R^(3b))C(O)OR^(3d),N(R^(3b))C(O)NR^(3b)R^(3c), N(R^(3b))SO₂NR^(3b)R^(3c), andN(R^(3b))C(NR^(3b)R^(3c))═NR^(3b)R^(3c); Y² is C(O), S(O)₂, or CR⁴R⁵; R⁴is H, deuterium, C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; R⁵ is H,deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆haloalkyl, —C(O)R^(5a), —C(O)OR^(5a), —C(O)NR^(5b)R^(5c), S(O)R^(5d),—S(O)₂R^(5a), —S(O)₂NR^(5b)R^(5c), or G¹; wherein the C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted orsubstituted with 1 or 2 substituents independently selected from thegroup consisting of G¹, —CN, —C(O)R^(5a), —C(O)OR^(5a),—C(O)NR^(5b)R^(5c), —C(O)N(R^(5b))NR^(5b)R^(5c), —S(O)R^(5d),—S(O)₂R^(5a), —S(O)₂NR^(5b)R⁵, —OR^(5a), —OC(O)R^(5d), —NR^(5b)R^(5c),N(R^(5b))C(O)R^(5d), N(R^(5b))SO₂R^(5d), N(R^(5b))C(O)OR^(5d),N(R^(5b))C(O)NR^(5b)R^(5d), N(R^(5b))SO₂NR^(5b)R^(5c), andN(R^(5b))C(NR^(5b)R^(5c))═NR^(5b)R^(5c); R^(3a), R^(3b), R^(3c), R^(5a),and R^(5b), at each occurrence, are each independently H, C₁-C₆ alkyl,C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, or —(C₁-C₆alkylenyl)-G¹; R^(5c), at each occurrence, is independently H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, —(C₁-C₆alkylenyl)-G¹, —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(a), or—(C₁-C₆ alkylenyl)-C(O)OR^(a); R^(3d), at each occurrence, isindependently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, G¹, or —(C₁-C₆ alkylenyl)-G¹; R^(5d), at each occurrence, isindependently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, G¹, —(C₁-C₆ alkylenyl)-G¹, —(C₁-C₆ alkylenyl)-NR^(c)R^(d), or—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)); G¹, at each occurrence, isindependently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl; and each G¹ is optionally substituted with 1, 2, 3, 4, or5 R^(1g) groups; R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, C₁-C₆ haloalkyl, —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c),—S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), or G²; wherein the C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted orsubstituted with 1 or 2 substituents independently selected from thegroup consisting of G², —CN, —C(O)R^(6a), —C(O)OR^(6a),—C(O)NR^(6b)R^(6c), —C(O)N(R^(6b))NR^(6b)R^(6c), —S(O)R^(6d),—S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), —OR^(6a), —OC(O)R^(6d),—NR^(6b)R^(6c), N(R^(6b))C(O)R^(6d), N(R^(6b))SO₂R^(6d),N(R^(6b))C(O)OR^(6d), N(R^(6b))C(O)NR^(6b)R^(6c),N(R^(6b))SO₂NR^(6b)R^(6c), and N(R^(6b))C(NR^(6b)R^(6c))═NR^(6b)R^(6c);R^(6a), R^(6b), and R^(6c), at each occurrence, are each independentlyH, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G², —(C₁-C₆alkylenyl)-G², —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a),—(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a),—(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆ alkylenyl)-C(O)NR R^(d), —(C₁-C₆alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); R^(6d), at each occurrence, isindependently alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G²,—(C₁-C₆ alkylenyl)-G², —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); G², at each occurrence, isindependently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl; and each G² is optionally substituted with 1, 2, 3, 4, or5 R^(2g) groups; A¹ is C(R⁷) or N; A² is C(R⁸) or N; A³ is C(R⁹) or N;and A⁴ is C(R¹⁰) or N; wherein zero, one, or two of A¹, A², A³, and A⁴are N; R⁷, R⁸, and R⁹, are each independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, —OR^(y1),—OC(O)R^(y2), —OC(O)NR^(y3)R^(y4), —SR^(y1), —S(O)₂R^(y1),—S(O)₂NR^(y3)R^(y4), —C(O)R^(y1), —C(O)OR^(y1), —C(O)NR^(y3)R^(y4),—NR^(y3)R^(y4), —N(R^(y3))C(O)R^(y2), —N(R^(y3))S(O)₂R^(y2),—N(R^(y3))C(O)O(R^(y2)), —N(R^(y3))C(O)NR^(y3)R^(y4),—N(R^(y3))S(O)₂NR³R^(y4), G³, —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆alkylenyl)-OR^(y1), —(C₁-C₆ alkylenyl)-OC(O)R², —(C₁-C₆alkylenyl)-OC(O)NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-S(O)₂R^(y1), —(C₁-C₆alkylenyl)-S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-C(O)R¹, —(C₁-C₆alkylenyl)-C(O)OR¹, —(C₁-C₆ alkylenyl)-C(O)NR^(y3)R⁴, —(C₁-C₆alkylenyl)-NR^(y3)R⁴, —(C₁-C₆ alkylenyl)-N(R^(y3))C(O)R^(y2), —(C₁-C₆alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆alkylenyl)-N(R^(y3))C(O)O(R^(y2)), —(C₁-C₆alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-N(R^(y3))S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-CN, or—(C₁-C₆ alkylenyl)-G³; R^(y1), R^(y3), and R^(y4), at each occurrence,are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ haloalkyl, G³, —(C₁-C₆ alkylenyl)-G³, —(C₁-C₆ alkylenyl)-OR^(a),—(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d),—(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); R^(y2), at each occurrence, is independently C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G³, —(C₁-C₆alkylenyl)-G³, —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a),—(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a),—(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d),—(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); G³, at each occurrence, isindependently aryl, heteroaryl, cycloalkyl, cycloalkenyl, orheterocycle; and each G³ group is optionally substituted with 1, 2, 3,4, or 5 R^(4g) groups; R¹⁰ is H, C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl,or —CN; R^(1g), R^(2g), and R⁴, at each occurrence, is independentlyselected from the group consisting of oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, G^(2a), —OR^(a),—OC(O)R^(b), —OC(O)NR^(c)R^(d), —SR^(a), —S(O)₂R^(a), —S(O)₂NR^(c)R^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(d), —NR^(c)R^(d),—N(R^(e))C(O)R^(b), —N(R^(e))S(O)₂R^(b), —N(R^(e))C(O)O(R^(b)),—N(R^(e))C(O)NR^(c)R^(d), —N(R^(e))S(O)₂NR^(c)R^(d), —(C₁-C₆alkylenyl)-CN, —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(a),—(C₁-C₆ alkylenyl)-OC(O)R^(b), —(C₁-C₆ alkylenyl)-OC(O)NR^(c)R^(d),—(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d),—(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d), or —(C₁-C₆ alkylenyl)-CN; R^(a),R^(c), R^(d), and R^(e), at each occurrence, are each independently H,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2a),—(C₁-C₆ alkylenyl)-OR^(z1), —(C₁-C₆ alkylenyl)-NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-C(O)NR^(z3)R^(z4), or —(C₁-C₆ alkylenyl)-G²a; R^(b), at eachoccurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ haloalkyl, G^(2a), or —(C₁-C₆ alkylenyl)-G^(2a); G^(2a), at eachoccurrence, are each independently aryl, heteroaryl, heterocycle,cycloalkyl, or cycloalkenyl; and each G^(2a) group is optionallysubstituted with 1, 2, 3, 4, or 5 R^(3g) groups; R^(3g), at eachoccurrence, is independently oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, —OR^(z1), —OC(O)R^(z2),—OC(O)NR^(z3)R^(z4), —SR^(z1), —S(O)₂R^(z1), —S(O)₂NR^(z3)R^(z4),—C(O)R^(z1), —C(O)OR^(z1), —C(O)NR^(z3)R^(z4)—NR^(z3)R^(z4),—N(R^(z3))C(O)R^(z2), —N(R³)S(O)₂R^(z2), —N(R^(z3))C(O)O(R^(z2)),—N(R^(z3))C(O)NR^(z3)R^(z4), —N(R^(z3))S(O)₂NR³R⁴, —(C₁-C₆alkylenyl)-OR^(z1), —(C₁-C₆ alkylenyl)-OC(O)R^(z2), —(C₁-C₆alkylenyl)-OC(O)NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-S(O)₂R^(z1), —(C₁-C₆alkylenyl)-S(O)₂NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-C(O)R^(z1), —(C₁-C₆alkylenyl)-C(O)OR^(z1), —(C₁-C₆ alkylenyl)-C(O)NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-N(R^(z3))C(O)R^(z2),—(C₁-C₆ alkylenyl)-N(R^(z3))S(O)₂R^(z2), —(C₁-C₆alkylenyl)-N(R^(z3))C(O)O(R²), —(C₁-C₆alkylenyl)-N(R^(z3))C(O)NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-N(R^(z3))S(O)₂NR³R⁴, or —(C₁-C₆ alkylenyl)-CN; R^(z1),R^(z3), and R^(z4), at each occurrence, are each independently H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl; and R^(z2), ateach occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, or C₁-C₆ haloalkyl.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is C₁-C₃ alkyl. 3.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is H.
 4. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Y¹ is CH; Y³ is CR³; and Y² is CR⁴R⁵.5. The compound of claim 4, or a pharmaceutically acceptable saltthereof, wherein R³ is H, —CN, —C(O)R^(3a), —C(O)OR^(3a),—C(O)NR^(3b)R^(3c), or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl isoptionally substituted with a substituent selected from the groupconsisting of G¹, —NR^(3b)R^(3c), N(R^(3b))C(O)R^(3d),N(R^(3b))SO₂R^(3d), N(R^(3b))C(O)OR^(3d), N(R^(3b))C(O)NR^(3b)R^(3c),and N(R^(3b))SO₂NR^(3b)R^(3c).
 6. The compound of claim 4, or apharmaceutically acceptable salt thereof, wherein R⁴ is H or deuterium;and R⁵ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, —C(O)R^(5a), —C(O)OR^(5a), or G¹; wherein the C₁-C₆ alkyl,C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted orsubstituted with 1 or 2 substituents independently selected from thegroup consisting of G¹, —C(O)R^(5a), —C(O)OR^(5a), —C(O)NR^(5b)R^(5c),—C(O)N(R^(5b))NR^(5b)R^(5c), —OR^(5a), —OC(O)R^(5d), —NR^(5b)R^(5c),N(R^(5b))C(O)R^(5d), N(R^(5b))SO₂R^(5d), N(R^(5b))C(O)OR^(5d),N(R^(5b))C(O)NR^(5b)R^(5c), and N(R^(5b))SO₂NR^(5b)R^(5c).
 7. Thecompound of claim 4, or a pharmaceutically acceptable salt thereof,wherein R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, —C(O)R^(6a), —C(O)OR^(6a),—C(O)NR^(6b)R^(6c), —S(O)₂R^(6a), or G²; wherein the C₁-C₆ alkyl and theC₂-C₆ alkenyl are each independently unsubstituted or substituted with 1or 2 substituents independently selected from the group consisting ofG², —CN, —C(O)OR^(6a), —NR^(6b)R^(6c), N(R^(6b))C(O)R^(6d),N(R^(6b))SO₂R^(6d), N(R^(6b))C(O)OR^(6d), N(R^(6b))C(O)NR^(6b)R^(6c),and N(R^(6b))SO₂NR^(6b)R^(6c).
 8. The compound of claim 4, or apharmaceutically acceptable salt thereof, wherein A¹ is C(R⁷), A² isC(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ isC(R⁹), and A⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).
 9. The compound of claim 4, or a pharmaceutically acceptablesalt thereof, wherein R⁹ is H, C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl,—CN, —S(O)₂R^(y1), —S(O)₂NR^(y3)R⁴, —C(O)NR^(y3)R^(y4), —NR^(y3)R^(y4),—N(R^(y3))C(O)R^(y2), —N(R^(y3))S(O)₂R^(y2), —N(R^(y3))C(O)O(R^(y2)),—N(R^(y3))C(O)NR^(y3)R^(y4), —N(R^(y3))S(O)₂NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-S(O)₂R^(y1), —(C₁-C₆ alkylenyl)-S(O)₂NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-C(O)NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-N(R³)C(O)R^(y2), —(C₁-C₆ alkylenyl)-N(R^(y3))S(O)₂R^(y2),—(C₁-C₆ alkylenyl)-N(R^(y3))C(O)O(R^(y2)), —(C₁-C₆alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), or —(C₁-C₆alkylenyl)-N(R³)S(O)₂NR^(y3)R⁴.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is C₁-C₃ alkyl; R²is H; Y¹ is CH; Y³ is CR³; and Y² is CR⁴R⁵.
 11. The compound of claim10, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H ordeuterium; and R⁵ is C₂-C₆ alkenyl optionally substituted with a G¹group, or R⁵ is H, deuterium, C₁-C₆ alkyl, —C(O)R^(5a), —C(O)OR^(5a), orG¹; wherein the C₁-C₆ alkyl is unsubstituted or substituted with asubstituent selected from the group consisting of G¹, —C(O)R^(5a),—C(O)OR^(5a), —C(O)NR^(5b)R^(5c), —C(O)N(R^(5b))NR^(5b)R^(5c), —OR^(5a),—OC(O)R^(5d), —NR^(5b)R^(5c), andN(R^(5b))C(NR^(5b)R^(5c))═NR^(5b)R^(5c).
 12. The compound of claim 10,or a pharmaceutically acceptable salt thereof, wherein R³ is H,—C(O)R^(3a), or —C(O)NR^(3b)R^(3c).
 13. The compound of claim 10, or apharmaceutically acceptable salt thereof, wherein R⁶ is H, C₁-C₆ alkyl,—C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c), —S(O)₂R^(6a), or G²;wherein the C₁-C₆ alkyl is unsubstituted or substituted with asubstituent selected from the group consisting of G² and —C(O)OR^(6a).14. The compound of claim 10, or a pharmaceutically acceptable saltthereof, wherein R⁹ is H, C₁-C₆ alkyl, halogen, —S(O)₂R^(y1),—S(O)₂NR^(y3)R^(y4), —NR^(y3)R^(y4), —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆alkylenyl)-S(O)₂R^(y1).
 15. The compound of claim 10, or apharmaceutically acceptable salt thereof, wherein A¹ is C(R⁷), A² isC(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ isC(R⁹), and A⁴ is C(R¹⁰); or A¹ is N, A² is C(R⁸), A³ is N, and A⁴ isC(R¹⁰).
 16. The compound of claim 15, or a pharmaceutically acceptablesalt thereof, wherein R¹ is methyl; R⁴ is H or deuterium; R⁷ is H,halogen, C₁-C₃ alkyl, or optionally substituted cyclopropyl; R⁸ is H,C₁-C₆ alkyl, halogen, C₁-C₆ haloalkyl, —CN, optionally substitutedheterocycle, —C(O)NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-NR^(y3)R^(y4),—(C₁-C₆ alkylenyl)-N(R³)C(O)R^(y2), —(C₁-C₆alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆ alkylenyl)-N(R³)C(O)O(R^(y2)),—(C₁-C₆ alkylenyl)-N(R³)C(O)NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-N(R^(y3))S(O)₂NR^(y3)R^(y4), or —(C₁-C₆ alkylenyl)-G³ whereinG³ is optionally substituted heterocycle; and R¹⁰ is H, C₁-C₃ alkyl, orhalogen.
 17. The compound of claim 16, or a pharmaceutically acceptablesalt thereof, wherein R³ is H or —C(O)NR^(3b)R^(3c).
 18. The compound ofclaim 16, or a pharmaceutically acceptable salt thereof, wherein R⁵ isH, deuterium, or C₁-C₆ alkyl optionally substituted with a substituentselected from the group consisting of —C(O)OR^(5a) and OR^(5a).
 19. Thecompound of claim 16, or a pharmaceutically acceptable salt thereof,wherein R⁶ is —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c), G², orC₁-C₆ alkyl which is unsubstituted or substituted with a G² group. 20.The compound of claim 16, or a pharmaceutically acceptable salt thereof,wherein R⁹ is halogen, —NR^(y3)R^(y4), —N(R^(y3))C(O)R^(y2),—N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆ alkylenyl)-S(O)₂R^(y1).
 21. Thecompound of claim 16, or a pharmaceutically acceptable salt thereof,wherein R⁷ is H or halogen; R⁸ is H; and R¹⁰ is H.
 22. The compound ofclaim 21, or a pharmaceutically acceptable salt thereof, wherein R⁹ ishalogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆ alkylenyl)-S(O)₂R^(y1). 23.The compound of claim 22, or a pharmaceutically acceptable salt thereof,wherein R⁶ is —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c), G², orC₁-C₆ alkyl which is unsubstituted or substituted with a G² group. 24.The compound of claim 23, or a pharmaceutically acceptable salt thereof,wherein R⁵ is H, deuterium, or C₁-C₆ alkyl optionally substituted with asubstituent selected from the group consisting of —C(O)OR^(5a) andOR^(5a).
 25. The compound of claim 24, or a pharmaceutically acceptablesalt thereof, wherein R³ is H or —C(O)NR^(3b)R^(3c).
 26. The compound ofclaim 25, or a pharmaceutically acceptable salt thereof, wherein R^(3b)and R^(3c) are each independently H or C₁-C₆ alkyl; R^(5a) is C₁-C₆alkyl; R^(y1) and R^(y2) are C₁-C₆ alkyl; and R^(y3) is H.
 27. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein A¹ is C(R⁷), A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰).
 28. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein A¹ is N, A² is C(R⁸), A³ is C(R⁹), and A⁴ is C(R¹⁰).
 29. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein A¹ is N, A² is C(R⁸), A³ is N, and A⁴ is C(R¹⁰).
 30. Thecompound of claim 15, or a pharmaceutically acceptable salt thereof,wherein R¹ is methyl; R³ is H, —C(O)NR^(3b)R^(3c), —CN, or C₁-C₆ alkylwhich is substituted with a G¹ group; wherein G¹ is an optionallysubstituted C₄-C₆ heterocycle; R⁴ is H or deuterium; R⁷ is H, halogen,—CN, C₁-C₃ alkyl, or optionally substituted cyclopropyl; R⁸ is H; R⁹ ishalogen, —N(R^(y3))S(O)₂R^(y2), or —(C₁-C₆ alkylenyl)-S(O)₂R^(y1); andR¹⁰ is H.
 31. The compound of claim 30, or a pharmaceutically acceptablesalt thereof, wherein R⁵ is H; and R⁶ is phenyl, pyridinyl, orcyclohexyl; each of which is optionally substituted; or R⁶ is—C(O)O(C₁-C₆ alkyl); or R⁶ is —CH₂— (optionally substitutedtetrahydropyranyl).
 32. The compound of claim 15, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is methyl; R³ is G¹; R⁴ is H ordeuterium; R⁷ is H, halogen, —CN, C₁-C₃ alkyl, or optionally substitutedcyclopropyl; R⁸ is H; R⁹ is —S(O)₂R^(y1), —N(R^(y3))S(O)₂R^(y2), or—(C₁-C₆ alkylenyl)-S(O)₂R^(y1); and R¹⁰ is H.
 33. The compound of claim15, or a pharmaceutically acceptable salt thereof, wherein R¹ is methyl;R³ is G¹; wherein G¹ is optionally substituted heteroaryl; R⁴ is H ordeuterium; R⁷ is H, halogen, —CN, C₁-C₃ alkyl, or optionally substitutedcyclopropyl; R⁸ is H; R⁹ is —S(O)₂R^(y1), —N(R^(y3))S(O)₂R^(y2), or—(C₁-C₆ alkylenyl)-S(O)₂R^(y1); R¹⁰ is H; and R⁵ is H.
 34. A compound offormula (I) or a pharmaceutically acceptable salt thereof,

wherein Y¹ is N orCH; R¹ is CD3, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; R² isH or C₁-C₃ alkyl; Y³ is N or CR³; R³ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —C(O)R^(3a), —C(O)OR^(3a),—C(O)NR^(3b)R^(3c), —S(O)R^(3d), —S(O)₂R^(3a), —S(O)₂NR^(3b)R^(3c), OrG; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are eachindependently unsubstituted or substituted with 1 or 2 substituentsindependently selected from the group consisting of G¹, —C(O)R^(3a),—C(O)OR^(3a), —C(O)NR^(3b)R^(3c), —C(O)N(R^(3b))NR^(3b)R^(3c),—S(O)R^(3d), —S(O)₂R^(3a), —S(O)₂NR^(3b)R^(3c), —OR^(3a), —OC(O)R^(3d),—NR^(3b)R^(3c), N(R^(3b))C(O)R^(3d), N(R^(3b))SO₂R^(3d),N(R^(3b))C(O)OR^(3d), N(R^(3b))C(O)NR^(3b)R^(3c)N(R^(3b))SO₂NR^(3b)R^(3c), and N(R^(3b))C(NR^(3b)R^(3c))═NR^(3b)R^(3c);Y² is C(O), S(O)₂, or CR⁴R⁵; R⁴ is H, deuterium, C₁-C₆ alkyl, halogen,or C₁-C₆ haloalkyl; R⁵ is H, deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —C(O)R^(5a), —C(O)OR^(5a),—C(O)NR^(5b)R^(5c), S(O)R^(5d), —S(O)₂R^(5a), —S(O)₂NR^(5b)R^(5c), orG¹; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are eachindependently unsubstituted or substituted with 1 or 2 substituentsindependently selected from the group consisting of G¹, —C(O)R^(5a),—C(O)OR^(5a), —C(O)NR^(5b)R^(5c), —C(O)N(R^(5b))NR^(5b)R^(5c),—S(O)R^(5d), —S(O)₂R^(5a), —S(O)₂NR^(5b)R^(5c), —OR^(5a), —OC(O)R^(5d),—NR^(5b)R^(5c), N(R^(5b))C(O)R^(5d), N(R^(5b))SO₂R^(5d),N(R^(5b))C(O)OR^(5d), N(R^(5b))C(O)NR^(5b)R^(5c),N(R^(5b))SO₂NR^(5b)R^(5c), and N(R^(5b))C(NR^(5b)R^(5c))═NR^(5b)R^(5c);R^(3a), R^(3b), R^(3c), R^(5a), R^(5b), and R^(5c), at each occurrence,are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ haloalkyl, G¹, or —(C₁-C₆ alkylenyl)-G¹; R^(3d) and R^(5d), ateach occurrence, are each independently C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, or —(C₁-C₆ alkylenyl)-G¹; G¹, ateach occurrence, is independently aryl, heteroaryl, heterocycle,cycloalkyl, or cycloalkenyl; and each G¹ is optionally substituted with1, 2, 3, 4, or 5 R^(1g) groups; R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —C(O)R^(6a), —C(O)OR^(6a),—C(O)NR^(6b)R^(6c), —S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), or G²; whereinthe C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are each independentlyunsubstituted or substituted with 1 or 2 substituents independentlyselected from the group consisting of G², —C(O)R^(6a), —C(O)OR^(6a),—C(O)NR^(6b)R^(6c), —C(O)N(R^(6b))NR^(6b)R^(6c), —S(O)R^(6d),—S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), —OR^(6a), —OC(O)R^(6d),—NR^(6b)R^(6c), N(R^(6b))C(O)R^(6d), N(R^(6b))SO₂R^(6d),N(R^(6b))C(O)OR^(6d), N(R^(6b))C(O)NR^(6b)R^(6c),N(R^(6b))SO₂NR^(6b)R^(6c), and N(R^(6b))C(NR^(6b)R^(6c))═NR^(6b)R^(6c);R^(6a), R^(6b), and R^(6c), at each occurrence, are each independentlyH, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G², —(C₁-C₆alkylenyl)-G², —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a),—(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a),—(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d),—(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); R^(6d), at each occurrence, isindependently alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G²,—(C₁-C₆ alkylenyl)-G², —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); G², at each occurrence, isindependently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl; and each G² is optionally substituted with 1, 2, 3, 4, or5 R^(2g) groups; A¹ is C(R⁷) or N; A² is C(R⁸) or N; A³ is C(R⁹) or N;and A⁴ is C(R¹⁰) or N; wherein zero, one, or two of A¹, A², A³, and A⁴are N; R⁷, R⁸, and R⁹, are each independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, —OR^(y1),—OC(O)R^(y2), —OC(O)NR^(y3)R^(y4), —SR^(y1), —S(O)₂R 1,—S(O)₂NR^(y3)R^(y4), —C(O)R^(y1), —C(O)OR^(y1), —C(O)NR^(y3)R^(y4),—NR^(y3)R^(y4), —N(R^(y3))C(O)R^(y2), —N(R^(y3))S(O)₂R^(y2),—N(R^(y3))C(O)O(R^(y2)), —N(R^(y3))C(O)NR^(y3)R^(y4),—N(R^(y3))S(O)₂NR³R^(y4), G³, —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆alkylenyl)-OR^(y1), —(C₁-C₆ alkylenyl)-OC(O)R², —(C₁-C₆alkylenyl)-OC(O)NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-S(O)₂R^(y1), —(C₁-C₆alkylenyl)-S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-C(O)R¹, —(C₁-C₆alkylenyl)-C(O)OR¹, —(C₁-C₆ alkylenyl)-C(O)NR^(y3)R⁴, —(C₁-C₆alkylenyl)-NR^(y3)R⁴, —(C₁-C₆ alkylenyl)-N(R^(y3))C(O)R^(y2), —(C₁-C₆alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆alkylenyl)-N(R^(y3))C(O)O(R^(y2)), —(C₁-C₆alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-N(R^(y3))S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-CN, or—(C₁-C₆ alkylenyl)-G³; R^(y1), R^(y3), and R^(y4), at each occurrence,are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ haloalkyl, G³, —(C₁-C₆ alkylenyl)-G³, —(C₁-C₆ alkylenyl)-OR^(a),—(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d),—(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); R^(y2), at each occurrence, is independently C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G³, —(C₁-C₆alkylenyl)-G³, —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a),—(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a),—(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d),—(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); G³, at each occurrence, isindependently aryl, heteroaryl, cycloalkyl, cycloalkenyl, orheterocycle; and each G³ group is optionally substituted with 1, 2, 3,4, or 5 R^(4g) groups; R¹⁰ is H, C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl,or —CN; R^(1g), R^(2g), and R⁴, at each occurrence, is independentlyselected from the group consisting of oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, G^(2a), —OR^(a),—OC(O)R^(b), —OC(O)NR^(c)R^(d), —SR^(a), —S(O)₂R^(a), —S(O)₂NR^(c)R^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(d), —NR^(c)R^(d),—N(R^(e))C(O)R^(b), —N(R^(e))S(O)₂R^(b), —N(R^(e))C(O)O(R^(b)),—N(R^(e))C(O)NR^(c)R^(d), —N(R^(e))S(O)₂NR^(c)R^(d), —(C₁-C₆alkylenyl)-CN, —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(a),—(C₁-C₆ alkylenyl)-OC(O)R^(b), —(C₁-C₆ alkylenyl)-OC(O)NR^(c)R^(d),—(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d),—(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d), or —(C₁-C₆ alkylenyl)-CN; R^(a),R^(c), R^(d), and R^(e), at each occurrence, are each independently H,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2a), or—(C₁-C₆ alkylenyl)-G^(2a); R^(b), at each occurrence, is independentlyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2a), or—(C₁-C₆ alkylenyl)-G^(2a); G^(2a), at each occurrence, are eachindependently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl; and each G^(2a) group is optionally substituted with 1, 2,3, 4, or 5 R^(3g) groups; R^(3g), at each occurrence, is independentlyoxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆haloalkyl, —CN, NO₂, —OR^(z1), —OC(O)R^(z2), —OC(O)NR^(z3)R^(z4),—SR^(z1), —S(O)₂R^(z1), —S(O)₂NR^(z3)R^(z4), —C(O)R^(z1), —C(O)OR^(z1),—C(O)NR^(z3)R^(z4), —NR^(z3)R^(z4), —N(R^(z3))C(O)R^(z2), —N(R³)S(O)₂R²,—N(R^(z3))C(O)O(R^(z2)), —N(R^(z3))C(O)NR^(z3)R^(z4),—N(R^(z3))S(O)₂NR³R⁴, —(C₁-C₆ alkylenyl)-OR^(z1), —(C₁-C₆alkylenyl)-OC(O)R^(z2), —(C₁-C₆ alkylenyl)-OC(O)NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-S(O)₂R^(z1), —(C₁-C₆ alkylenyl)-S(O)₂NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-C(O)R^(z1), —(C₁-C₆ alkylenyl)-C(O)OR^(z1), —(C₁-C₆alkylenyl)-C(O)NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-N(R^(z3))C(O)R^(z2), —(C₁-C₆ alkylenyl)-N(R^(z3))S(O)₂R^(z2),—(C₁-C₆ alkylenyl)-N(R^(z3))C(O)O(R²), —(C₁-C₆alkylenyl)-N(R^(z3))C(O)NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-N(R^(z3))S(O)₂NR³R⁴, or —(C₁-C₆ alkylenyl)-CN; R^(z1),R^(z3), and R^(z4), at each occurrence, are each independently H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl; and R^(z2), ateach occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, or C₁-C₆ haloalkyl.
 35. A compound of formula (I) or apharmaceutically acceptable salt thereof,

wherein Y¹ is N or CH; R¹ is CD3, C₁-C₃ alkyl, or C₁-C₃ haloalkyl; R² isH or C₁-C₃ alkyl; Y³ is N or CR³; R³ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, —C(O)R^(3a), —C(O)OR^(3a),—C(O)NR^(3b)R^(3c), —S(O)R^(3d), —S(O)₂R^(3a), —S(O)₂NR^(3b)R^(3c), orG¹; wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are eachindependently unsubstituted or substituted with 1 or 2 substituentsindependently selected from the group consisting of G¹, —CN,—C(O)R^(3a), —C(O)OR^(3a), —C(O)NR^(3b)R^(3c),—C(O)N(R^(3b))NR^(3b)R^(3c), —S(O)R^(3d), —S(O)₂R^(3a),—S(O)₂NR^(3b)R^(3c), —OR^(3a), —OC(O)R^(3d), —NR^(3b)R^(3c),N(R^(3b))C(O)R^(3d), N(R^(3b))SO₂R^(3d), N(R^(3b))C(O)OR^(3d),N(R^(3b))C(O)NR^(3b)R^(3c), N(R^(3b))SO₂NR^(3b)R^(3c), andN(R^(3b))C(NR^(3b)R^(3c))═NR^(3b)R^(3c); Y² is C(O), S(O)₂, or CR⁴R⁵; R⁴is H, deuterium, C₁-C₆ alkyl, halogen, or C₁-C₆ haloalkyl; R⁵ is H,deuterium, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆haloalkyl, —C(O)R^(5a), —C(O)OR^(5a), —C(O)NR^(5b)R^(5c), S(O)R^(5d),—S(O)₂R^(a), —S(O)₂NR^(5b)R^(5c), or G¹; wherein the C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted orsubstituted with 1 or 2 substituents independently selected from thegroup consisting of G¹, —C(O)R^(5a), —C(O)OR^(5a), —C(O)NR^(5b)R^(5c),—C(O)N(R^(5b))NR^(5b)R^(5c), —S(O)R^(5d), —S(O)₂R^(5a),—S(O)₂NR^(5b)R^(5c), —OR^(5a), —OC(O)R^(5d), —NR^(5b)R^(5c),N(R^(5b))C(O)R^(5d), N(R^(5b))SO₂R^(5d), N(R^(5b))C(O)OR^(5d),N(R^(5b))C(O)NR^(5b)R^(5c), N(R^(5b))SO₂NR^(5b)R^(5c), andN(R^(5b))C(NR^(5b)R^(5c))═NR^(5b)R^(5c); R^(3a), R^(3b), R^(3c), R^(5a),and R^(5b), at each occurrence, are each independently H, C₁-C₆ alkyl,C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, or —(C₁-C₆alkylenyl)-G¹; R^(5c), at each occurrence, is independently H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G¹, —(C₁-C₆alkylenyl)-G¹, —(C₁-C₆ alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(a), or—(C₁-C₆ alkylenyl)-C(O)OR^(a); R^(3d), at each occurrence, isindependently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, G¹, or —(C₁-C₆ alkylenyl)-G¹; R^(5d), at each occurrence, isindependently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, G¹, —(C₁-C₆ alkylenyl)-G¹, —(C₁-C₆ alkylenyl)-NR^(c)R^(d), or—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)); G¹, at each occurrence, isindependently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl; and each Gi is optionally substituted with 1, 2, 3, 4, or5 R^(1g) groups; R⁶ is H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, C₁-C₆ haloalkyl, —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c),—S(O)₂R^(6a), —S(O)₂NR^(6b)R^(6c), or G²; wherein the C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are each independently unsubstituted orsubstituted with 1 or 2 substituents independently selected from thegroup consisting of G², —C(O)R^(6a), —C(O)OR^(6a), —C(O)NR^(6b)R^(6c),—C(O)N(R^(6b))NR^(6b)R^(6c), —S(O)R^(6d), —S(O)₂R^(6a),—S(O)₂NR^(6b)R^(6c), —OR^(6a), —OC(O)R^(6d), —NR^(6b)R^(6c),N(R^(6b))C(O)R^(6d), N(R^(6b))SO₂R^(6d), N(R^(6b))C(O)OR^(6d),N(R^(6b))C(O)NR^(6b)R^(6c), N(R^(6b))SO₂NR^(6b)R^(6c), andN(R^(6b))C(NR^(6b)R^(6c))═NR^(6b)R^(6c); R^(6a), R^(6b), and R^(6c), ateach occurrence, are each independently H, alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, haloalkyl, G², —(C₁-C₆ alkylenyl)-G², —(C₁-C₆alkylenyl)-OR^(a), —(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆alkylenyl)-C(O)OR^(a), —(C₁-C₆ alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆alkylenyl)-NR^(c)R^(d), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); R^(6d), at each occurrence, isindependently alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, haloalkyl, G²,—(C₁-C₆ alkylenyl)-G², —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); G², at each occurrence, isindependently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl; and each G² is optionally substituted with 1, 2, 3, 4, or5 R^(2g) groups; A¹ is C(R⁷) or N; A² is C(R⁸) or N; A³ is C(R⁹) or N;and A⁴ is C(R¹⁰) or N; wherein zero, one, or two of A¹, A², A³, and A⁴are N; R⁷, R⁸, and R⁹, are each independently H, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, —OR^(y1),—OC(O)R^(y2), —OC(O)NR^(y3)R^(y4), —SR^(y1), —S(O)₂R 1, —S(O)₂NR^(y3)R⁴,—C(O)R^(y1), —C(O)OR 1, —C(O)NR^(y3)R^(y4), —NR^(y3)R^(y4),—N(R^(y3))C(O)R^(y2), —N(R^(y3))S(O)₂R^(y2), —N(R^(y3))C(O)O(R^(y2)),—N(R^(y3))C(O)NR^(y3)R^(y4), —N(R^(y3))S(O)₂NR³R^(y4), G³, —(C₁-C₆alkylenyl)-CN, —(C₁-C₆ alkylenyl)-OR^(y1), —(C₁-C₆ alkylenyl)-OC(O)R²,—(C₁-C₆ alkylenyl)-OC(O)NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-S(O)₂R^(y1),—(C₁-C₆ alkylenyl)-S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-C(O)R^(y1),—(C₁-C₆ alkylenyl)-C(O)OR^(y1), —(C₁-C₆ alkylenyl)-C(O)NR^(y3)R⁴,—(C₁-C₆ alkylenyl)-NR^(y3)R⁴, —(C₁-C₆ alkylenyl)-N(R^(y3))C(O)R^(y2),—(C₁-C₆ alkylenyl)-N(R^(y3))S(O)₂R^(y2), —(C₁-C₆alkylenyl)-N(R^(y3))C(O)O(R^(y2)), —(C₁-C₆alkylenyl)-N(R^(y3))C(O)NR^(y3)R^(y4), —(C₁-C₆alkylenyl)-N(R^(y3))S(O)₂NR^(y3)R^(y4), —(C₁-C₆ alkylenyl)-CN, or—(C₁-C₆ alkylenyl)-G³; R^(y1), R^(y3), and R^(y4), at each occurrence,are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ haloalkyl, G³, —(C₁-C₆ alkylenyl)-G³, —(C₁-C₆ alkylenyl)-OR^(a),—(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d),—(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); R^(y2), at each occurrence, isindependently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆haloalkyl, G³, —(C₁-C₆ alkylenyl)-G³, —(C₁-C₆ alkylenyl)-OR^(a), —(C₁-C₆alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d), —(C₁-C₆alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), or —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d); G³, at each occurrence, isindependently aryl, heteroaryl, cycloalkyl, cycloalkenyl, orheterocycle; and each G³ group is optionally substituted with 1, 2, 3,4, or 5 R^(4g) groups; R¹⁰ is H, C₁-C₃ alkyl, halogen, C₁-C₃ haloalkyl,or —CN; R^(1g), R^(2g), and R⁴, at each occurrence, is independentlyselected from the group consisting of oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, C₁-C₆ haloalkyl, —CN, NO₂, G^(2a), —OR^(a),—OC(O)R^(b), —OC(O)NR^(c)R^(d), —SR^(a), —S(O)₂R^(a), —S(O)₂NR^(c)R^(d),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(c)R^(d), —NR^(c)R^(d),—N(R^(e))C(O)R^(b), —N(R^(e))S(O)₂R^(b), —N(R^(e))C(O)O(R^(b)),—N(R^(e))C(O)NR^(c)R^(d), —N(R^(e))S(O)₂NR^(c)R^(d), —(C₁-C₆alkylenyl)-CN, —(C₁-C₆ alkylenyl)-G^(2a), —(C₁-C₆ alkylenyl)-OR^(a),—(C₁-C₆ alkylenyl)-OC(O)R^(b), —(C₁-C₆ alkylenyl)-OC(O)NR^(c)R^(d),—(C₁-C₆ alkylenyl)-S(O)₂R^(a), —(C₁-C₆ alkylenyl)-S(O)₂NR^(c)R^(d),—(C₁-C₆ alkylenyl)-C(O)R^(a), —(C₁-C₆ alkylenyl)-C(O)OR^(a), —(C₁-C₆alkylenyl)-C(O)NR^(c)R^(d), —(C₁-C₆ alkylenyl)-NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))C(O)R^(b), —(C₁-C₆ alkylenyl)-N(R^(e))S(O)₂R^(b),—(C₁-C₆ alkylenyl)-N(R^(e))C(O)O(R^(b)), —(C₁-C₆alkylenyl)-N(R^(e))C(O)NR^(c)R^(d), —(C₁-C₆alkylenyl)-N(R^(e))S(O)₂NR^(c)R^(d), or —(C₁-C₆ alkylenyl)-CN; R^(a),R^(c), R^(d), and R^(e), at each occurrence, are each independently H,C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2a), or—(C₁-C₆ alkylenyl)-G^(2a); R^(b), at each occurrence, is independentlyC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl, G^(2a), or—(C₁-C₆ alkylenyl)-G^(2a); G^(2a), at each occurrence, are eachindependently aryl, heteroaryl, heterocycle, cycloalkyl, orcycloalkenyl; and each G^(2a) group is optionally substituted with 1, 2,3, 4, or 5 R^(3g) groups; R^(3g), at each occurrence, is independentlyoxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, C₁-C₆haloalkyl, —CN, NO₂, —OR^(z1), —OC(O)R^(z2), —OC(O)NR^(z3)R^(z4),—SR^(z1), —S(O)₂R^(z1), —S(O)₂NR^(z3)R^(z4), —C(O)R^(z1), —C(O)OR^(z1),—C(O)NR^(z3)R^(z4), —NR^(z3)R^(z4), —N(R^(z3))C(O)R^(z2),—N(R^(z3))S(O)₂R², —N(R^(z3))C(O)O(R^(z2)), —N(R^(z3))C(O)NR^(z3)R^(z4),—N(R^(z3))S(O)₂NR³R⁴, —(C₁-C₆ alkylenyl)-OR^(z1), —(C₁-C₆alkylenyl)-OC(O)R^(z2), —(C₁-C₆ alkylenyl)-OC(O)NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-S(O)₂R^(z1), —(C₁-C₆ alkylenyl)-S(O)₂NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-C(O)R^(z1), —(C₁-C₆ alkylenyl)-C(O)OR^(z1), —(C₁-C₆alkylenyl)-C(O)NR^(z3)R^(z4), —(C₁-C₆ alkylenyl)-NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-N(R^(z3))C(O)R^(z2), —(C₁-C₆ alkylenyl)-N(R^(z3))S(O)₂R^(z2),—(C₁-C₆ alkylenyl)-N(R^(z3))C(O)O(R^(z2)), —(C₁-C₆alkylenyl)-N(R^(z3))C(O)NR^(z3)R^(z4), —(C₁-C₆alkylenyl)-N(R^(z3))S(O)₂NR³R⁴, or —(C₁-C₆ alkylenyl)-CN; R^(z1),R^(z3), and R^(z4), at each occurrence, are each independently H, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or C₁-C₆ haloalkyl; and R^(z2), ateach occurrence, is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, or C₁-C₆ haloalkyl.
 36. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:4-(cyclopropylmethyl)-7-(isopropylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(cyclopropylmethyl)-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(cyclopropylmethyl)-3-ethyl-7-(ethylsulfonyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(1H)-one;10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;ethyl4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;4-(4-fluorophenyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(cyclopropylmethyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-7-sulfonamide;4-(4-fluorophenyl)-7,10-dimethyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(cyclopropylmethyl)-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;methyl3-(4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;4-(cyclopropylmethyl)-3-(2-methoxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;3-benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;methyl3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;10-methyl-7-((methylsulfonyl)methyl)-3-phenethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;3-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;(E)-3-(4-fluorostyryl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;7-amino-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;N-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide;N-(4-(2,4-difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide;4-butyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;tert-butyl3-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)pyrrolidine-1-carboxylate;10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-((4,4-difluorocyclohexyl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;tert-butyl4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)piperidine-1-carboxylate;10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydro-2H-pyran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4,4-difluorocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-fluorophenyl)-(3,3-²H₂)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;7-fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;4-(4-fluorophenyl)-7,10-dimethyl-3-phenyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;ethyl4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;tert-butyl4-(4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carbonyl)piperazine-1-carboxylate;10-methyl-7-((methylsulfonyl)methyl)-4-(pyrrolidin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(piperidin-4-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;7-fluoro-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;ethyl7-fluoro-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-3-carboxylate;4-(4-fluorophenyl)-3-(4-methoxypiperidine-1-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-fluorophenyl)-10-methyl-3-(4-methylpiperazine-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;5,7-difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;ethyl4-(4-fluorophenyl)-7,10-dimethyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulene-3-carboxylate;N-cyclopentyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;4-butyl-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;5,7-difluoro-10-methyl-4-propyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(cyclopropylmethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;methyl4-(5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)butanoate;5,7-difluoro-10-methyl-4-(3-phenylpropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(o-tolyl)-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;2-ethylhexyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;4-isobutyryl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;5,7-difluoro-10-methyl-4-phenethyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-((1Z,3E)-2,4-diphenylbuta-1,3-dien-1-yl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;4-(4-chlorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;4-(4-chlorophenyl)-10-methyl-2-(4-methylpiperazine-1-carbonyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;N-(2,6-dimethylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-(4-methoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-(4-ethylphenethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-propyl-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-(3-methoxybenzyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-(2-chloroethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-(cyclohexylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-(4-isopropylphenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-(2,6-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;N-(4-fluoro-3-(trifluoromethyl)phenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;ethyl4-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4-carboxamido)methyl)cyclohexanecarboxylate;N-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;10-methyl-7-((methylsulfonyl)methyl)-4-tosyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-([1,1′-biphenyl]-4-ylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-((4-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(phenylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-((2-methoxyphenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-((4-phenoxyphenyl)sulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-((4-fluorophenyl)sulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;methyl3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;4-(2,4-difluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,7,10-pentaazadibenzo[cd,f]azulen-11(10H)-one;(R)-ethyl4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;(S)-ethyl4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;2-methoxyethyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;ethyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;pentyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;4-chlorobutyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;naphthalen-2-yl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;p-tolyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;neopentyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;phenyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;4-fluorophenyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;2-methoxyphenyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;2-fluoroethyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;4-methoxyphenyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;but-2-yn-1-yl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide;4-(4-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(3-methoxypropanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-([1,1′-biphenyl]-4-carbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(3-cyclopentylpropanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2-(3-methoxyphenyl)acetyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-propionyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-4-(3-methylbutanoyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(3,3-dimethylbutanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(2-phenylacetyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-benzoyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-methoxybenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;methyl4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)-4-oxobutanoate;4-(2,4-difluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2-fluorobenzoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(1-naphthoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(cyclopropanecarbonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(3-phenylpropanoyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione;3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-methylpropanamide;3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N,N-dimethylpropanamide;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-morpholino-3-oxopropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(tetrahydro-2H-pyran-4-yl)propanamide;3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N′-methyl-N′-phenylpropanehydrazide;N-benzyl-3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamide;3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(1,1-dioxidotetrahydrothiophen-3-yl)propanamide;tert-butyl4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoyl)piperazine-1-carboxylate;tert-butyl4-(3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanamido)piperidine-1-carboxylate;4-(4-chlorophenyl)-N-ethyl-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;6-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)hexylacetate;3-(aminomethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;N-((((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)(dimethylamino)methylene)-N-methylmethanaminium;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-oxo-3-(piperazin-1-yl)propyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)-N-(piperidin-4-yl)propanamide;4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)butane-1,2-diyldiacetate; methyl5-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)pentanoate;tert-butyl(2-(((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)amino)-2-oxoethyl)carbamate;4-(2,4-difluorophenyl)-3-(6-hydroxyhexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)benzamide;1-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)-3-phenylurea;2-amino-N-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)acetamide;4-(2,4-difluorophenyl)-3-(3,4-dihydroxybutyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;4-(2,4-difluorophenyl)-3-(3-hydroxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-phenoxypropyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-3-(3-methoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-3-(3-ethoxypropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-((1-ethylpiperidin-3-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-ethoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;N-(2-cyanoethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;methyl2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamido)acetate;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-phenethyl-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;N-butyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;N-cyclohexyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;N-benzyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(3-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;4-(2,4-difluorophenyl)-N-isobutyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;4-(2,4-difluorophenyl)-N-(2-hydroxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-N-(oxazol-4-ylmethyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;N-(cyclopropylmethyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;4-(2,4-difluorophenyl)-N-(2-hydroxy-2-methylpropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;4-(2,4-difluorophenyl)-N-(1-(hydroxymethyl)cyclopropyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;4-(2,4-difluorophenyl)-10-methyl-N-(1-methylcyclopropyl)-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-(4-phenylbutyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxamide;4-(3,3-dimethylbutanoyl)-5,7-difluoro-10-methyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;tert-butyl((trans)-4-(10-methyl-7-(methylsulfonyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;4-((trans)-4-aminocyclohexyl)-10-methyl-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(cyclopropylsulfonyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;ethyl5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;4-(2,4-difluorophenyl)-10-methyl-3-(3-(methylamino)propyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-3-(3-(dimethylamino)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;2-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-7-yl)acetonitrile;4-(2,2-dimethyl-3-(pyrrolidin-1-yl)propyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;2-(3-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)pyrrolidin-1-yl)aceticacid;10-methyl-7-((methylsulfonyl)methyl)-4-(2-methyltetrahydrofuran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-4-(1-methylpiperidin-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(tetrahydro-2H-pyran-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-((1-isopropylpiperidin-4-yl)methyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(1-(2-oxotetrahydrofuran-3-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(1-methoxypropan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-methoxybutan-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-4-(1-methylpyrrolidin-3-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-4-(1-methylazepan-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(1-ethylpiperidin-3-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)benzonitrile;4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-2-(morpholinomethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;N-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;5-cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;tert-butyl(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;tert-butyl((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;4-(2,4-difluorophenyl)-3-(hydroxymethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-chlorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;4-(2,4-difluorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;4-(4-cyanophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;(S)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione;(R)-2-((4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)methyl)isoindoline-1,3-dione;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrile;10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;ethyl4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylate;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;10-methyl-7-((methylsulfonyl)methyl)-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-aminocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(3,5-difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(naphthalen-1-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-(3,3-²H₂)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-neopentyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((1-oxoisoindolin-2-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-3-(2,6-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-3-(3,5-dimethoxyphenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;3-(3,5-di-tert-butylphenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;methyl(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;methyl((trans)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;methyl((cis)-4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;2-(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)isoindoline-1,3-dione;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(tetrahydro-2H-pyran-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;benzyl(2-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)ethyl)carbamate;3-([1,1′-biphenyl]-2-yl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(quinolin-8-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;3-(4-(1H-imidazol-1-yl)phenyl)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-(3-(pyridin-2-yl)phenyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)benzonitrile;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;ethyl4-(2,4-difluorophenyl)-2-(ethylcarbamoyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-3-carboxylate;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide;4-(2,4-difluorophenyl)-N,10-dimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide;4-(2,4-difluorophenyl)-N,N,10-trimethyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carboxamide;N-(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)acetamide;10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-3-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(5-chloropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(1H-indazol-5-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-benzyl-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-5-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(pyridazin-3-ylmethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;(S)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;(R)-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3-((2-oxopyridin-1(2H)-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2-fluoropyridin-4-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-4-((1-methyl-1H-pyrazol-3-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(6-methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,2-dimethyl-3-morpholinopropyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(5-fluoropyrimidin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(pyrimidin-4-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2-(3-(dimethylamino)propoxy)benzyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;2-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)-2-phenylacetonitrile;2-(2-((10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)methyl)phenoxy)acetamide;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxylicacid;10-methyl-7-((methylsulfonyl)methyl)-4-(2-(pyridin-2-ylmethoxy)benzyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;(R)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-4-(pyridin-2-yl)-7-(pyrrolidin-1-ylsulfonyl)-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;(S)-7-(ethylsulfonyl)-10-methyl-4-(1-phenylethyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;(R)-methyl3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;(S)-methyl3-(4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;4-(2,4-difluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;(R)—N-ethyl-7-(ethylsulfonyl)-10-methyl-11-oxo-4-(1-phenylpropyl)-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-phenyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;and4-(4-fluorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one.37. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;methyl3-(4-(cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulen-3-yl)propanoate;4-(cyclopropylmethyl)-3-(2-methoxyethyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;N-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide;N-(4-(2,4-difluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide;10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4,4-difluorocyclohexyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-fluorophenyl)-(3,3-²H₂)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;7-fluoro-4-(4-fluorophenyl)-10-methyl-3,4-dihydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-11(10H)-one;5,7-difluoro-10-methyl-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;5,7-difluoro-10-methyl-4-propyl-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;4-(4-chlorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;10-methyl-7-((methylsulfonyl)methyl)-11-oxo-N-propyl-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxamide;ethyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;p-tolyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;4-fluorophenyl10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;and4-(3,3-dimethylbutanoyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one.38. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein the compound is selected from the group consisting of:4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;N-(4-(4-fluorophenyl)-10-methyl-11-oxo-3,4,10,11-tetrahydro-1H-1,4,5,10-tetraazadibenzo[cd,f]azulen-7-yl)ethanesulfonamide;10-methyl-7-((methylsulfonyl)methyl)-4-((tetrahydrofuran-3-yl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;ethyl5,7-difluoro-10-methyl-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulene-4(3H)-carboxylate;4-(4-chlorophenyl)-10-methyl-2-((4-methylpiperazin-1-yl)methyl)-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;N-ethyl-4-(4-fluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;5-cyclopropyl-4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;tert-butyl(4-(10-methyl-7-((methylsulfonyl)methyl)-11-oxo-10,11-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-4(3H)-yl)cyclohexyl)carbamate;4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(4-chlorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carbonitrile;4-(2,4-difluorophenyl)-N-ethyl-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamide;4-(2,4-difluorophenyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-5-carbonitrile;10-methyl-7-((methylsulfonyl)methyl)-4-(pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(3,5-difluoropyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;10-methyl-7-((methylsulfonyl)methyl)-4-(5-(trifluoromethyl)pyridin-2-yl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;4-(6-methoxypyridin-2-yl)-10-methyl-7-((methylsulfonyl)methyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one;and4-(4-chlorophenyl)-10-methyl-2-(1-methyl-1H-pyrazol-4-yl)-7-(methylsulfonyl)-3,4-dihydro-1H-1,4,10-triazadibenzo[cd,f]azulen-11(10H)-one.39. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 40. A method for treating cancer in a subjectcomprising administering a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof.
 41. The method ofclaim 40 wherein the cancer is selected from the group consisting of:acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia (monocytic, myeloblastic, adenocarcinoma,angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acutet-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladdercancer, brain cancer, breast cancer, bronchogenic carcinoma, cervicalcancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,chronic lymphocytic leukemia, chronic myelocytic (granulocytic)leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin, and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.
 42. A method for treating a disease or condition in asubject comprising administering a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof, wherein saiddisease or condition is selected from the group consisting of Addison'sdisease, acute gout, ankylosing spondylitis, asthma, atherosclerosis,Behcet's disease, bullous skin diseases, cardiac myopathy, cardiachypertrophy, chronic obstructive pulmonary disease (COPD), Crohn'sdisease, dermatitis, eczema, giant cell arteritis, glomerulonephritis,heart failure, hepatitis, hypophysitis, inflammatory bowel disease,Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis,myositis, nephritis, organ transplant rejection, osteoarthritis,pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primarybiliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis,scleritis, sclerosing cholangitis, sepsis systemic lupus erythematosus,Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes,ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener'sgranulomatosis.
 43. A method for treating a chronic kidney disease orcondition in a subject comprising administering a therapeuticallyeffective amount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof, to a subject in need thereof,wherein said disease or condition is selected from the group consistingof: diabetic nephropathy, hypertensive nephropathy, HIV-associatednephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focalsegmental glomerulosclerosis, membranous glomerulonephritis, minimalchange disease, polycystic kidney disease, and tubular interstitialnephritis.
 44. A method for treating an acute kidney disease orcondition in a subject comprising administering a therapeuticallyeffective amount of a compound of formula (I) according to claim 1 or apharmaceutically acceptable salt thereof, to a subject in need thereof,wherein said acute kidney disease or condition is selected from thegroup consisting of: ischemia-reperfusion induced kidney disease,cardiac and major surgery induced kidney disease, percutaneous coronaryintervention induced kidney disease, radio-contrast agent induced kidneydisease, sepsis induced kidney disease, pneumonia induced kidneydisease, and drug toxicity induced kidney disease.
 45. A method fortreating an acquired immunodeficiency syndrome (AIDS) in a subjectcomprising administering a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof.
 46. A method fortreating a disease or condition in a subject comprising administering atherapeutically effective amount of a compound of formula (I) accordingto claim 1 or a pharmaceutically acceptable salt thereof, to a subjectin need thereof, wherein said disease or condition is selected from thegroup consisting of: obesity, dyslipidemia, hypercholesterolemia,Alzheimer's disease, metabolic syndrome, hepatic steatosis, type IIdiabetes, insulin resistance, diabetic retinopathy, and diabeticneuropathy.
 47. A method of contraception in a male subject comprisingadministering a therapeutically effective amount of a compound offormula (I) according to claim 1 or a pharmaceutically acceptable saltthereof, to a subject in need thereof.